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Free Radicals Nitric Oxide and Inflammation Molecular
Biochemical and Clinical Aspects NATO Life and
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Author(s): Nitric Oxide, and Inflammation: Molecular, Biochemical, and
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Year: 2003
Language: english
FREE RADICALS, NITRIC OXIDE, AND INFLAMMATION:
MOLECULAR, BIOCHEMICAL, AND CLINICAL ASPECTS
NATO Science Series

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Series I: Life and Behavioural Sciences - Vol. 344 ISSN: 1566-7693

 Free Radicals, Nitric Oxide, and
Inflammation: Molecular,
Biochemical, and Clinical Aspects

Edited by

Aldo Tomasi
Department of Biomedical Science, School of Medicine,
University of Modena, Italy

Tomris Ozben
Department of Biochemistry, School of Medicine,
Akdeniz University, Antalya, Turkey

and

Vladimir P. Skulachev
A.N. Belozersky Institute of Physico-Chemical Biology,
Moscow State University, Russia

/OS
Press

Ohmsha

Amsterdam • Berlin • Oxford • Tokyo • Washington, DC

Published in cooperation with NATO Scientific Affairs Division

Proceedings of the NATO Advanced Study Institute on
Free Radicals, Nitric Oxide, and Inflammation: Molecular, Biochemical, and Clinical Aspects
23 September - 4 October 2001
Antalya, Turkey

© 2003, IOS Press

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, without prior written permission from the publisher.

ISBN 1 58603 243 7 (IOS Press)

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 Foreword
Inflammation is the local response of a complex organism to an injury that serves as a
mechanism initiating the elimination of noxious agents and of damaged tissues. It is now
well understood that damaging mechanisms at the basis of very common human
pathologies, such as atherosclerosis, neurodegenerative disesases, and cancer, i.e. the most
common human pathologies, are driven by the inflammatory process.
Free radicals, and the very special free radical nitric oxide, are playing a relevant role
in the pathogenesis of inflammation. The book reports topics taught and discussed during
the NATO Advanced Study Institute course held in Antalya, September 23–October 4
2001.
The initial chapters introduce to the general knowledge necessary to understand the
inflammatory process and the role played of free radical and oxidative stress. The interplay
between inflammatory molecules and cell signalling is also dealt with in depth. A second
part is dedicated to nitric oxide, redox regulation and antioxidant function in inflammation.
The final chapters are devoted to diseases where inflammation plays the dominant role:
septic shock, end-stage renal disease, neurodegenerative, ischemic and lung diseases.
This book, while not covering the whole gamut of the massive literature on
inflammation and human diseases, gives an updated and concise view on the major issues
concerning the pivotal role of inflammation in so many different human pathologies. At the
same time it gives directions for future paths of research leading to a control of the
pathologic process.

Aldo Tomasi, Tomris Ozben and Vladimir Skulachev,

Editors
This page intentionally left blank
 Contents
Foreword v

Alternative Functions of Mitochondria, V.P. Skulachev 1

The Enzymatic Systems in the Regulation of Free Radical Lipid Peroxidation,
V.Z. Lankin 8
Flavanols and Procyanidins as Modulators of Oxidation in vitro and in vivo,
• C.G. Fraga and C.I. Keen 24
Estimation of Oxidative and Lipids Peroxidation DNA Adduct in Urine and DNA.
Methodological Aspects and Application in Molecular Epidemiology,
H.E. Poulsen 34
Oxidative and Nitrosative Stress Mediated by Cyclosporine A in Endothelial Cells,
J. Navarro-Antolin and S. Lamas 39
Early Signaling with Iron and Copper in Ischemic Preconditioning of the Heart,
B. Vaisman, E. Berenshtein, C. Goldberg-Langerman, N. Kitrossky,
A.M. Konijn and M. Chevion 46
Multiple Mechanisms Regulating Endothelial Nitric Oxide Synthase,
A. W. Wyatt and G.E. Mann 60
Nitric Oxide. Its Generation, Reactions and Role in Physiology, T.M. Millar,
J.M. Kanczler, T. Bodamyali, C. Stevens and D.R. Blake 71
Redox-Regulated Glutathionylation of Transcription Factors: A Regulatory Mode
for Gene Expression, E. Pineda-Molina and S. Lamas 89
Sulphur-Containing Amino Acids, Glutathione and the Modulation of
Inflammation, F. Santangelo 102
Molecular Events of the Inflammation Process that are Affected by a-Tocopherol.
Antioxidants and Gene Expression in the Process of Inflammation and
Wound Repair, A. Azzi, J.-M. Zingg, T. Visarius and R. Ricciarelli 112
Redox Regulation, Cytokine, and Nitric Oxide in Inflammation, A. Tomasi,
S. Bergamini, C. Rota and A. lannone 119
Non-Traditional Cardiovascular Disease Risk Factors and Arterial Inflammatory
Response in End-Stage Renal Disease, T. Ozben 132
Significance of Reactive Oxygen Species for Neuronal Function,
A.A.Boldyrev 153
Protein Aggregates and the Development of Neurodegenerative Diseases,
A. Stolzing and T. Grune 170
Inflammatory Response of the Brain Following Cerebral Ischemia, T. Ozben 182
Carnosine as Natural Antioxidant and Neuroprotector: Biological Functions and
Possible Clinical Use, A.A. Boldyrev 202
Atherosclerosis as a Free Radical Pathology and Antioxidative Therapy of this Disease,
V.Z. Lankin and A.K. Tikhaze 218
H2O2 Sensors of Lungs and Blood Vessels and their Role in the Antioxidant Defense
of the Body, V.P. Skulachev 232
Oxidative Lung Injury, F.J. Kelly 237
Proper Design of Human Intervention Studies, Power Calculations, H.E. Poulsen 252

Author Index 255

This page intentionally left blank
Free Radicals, Nitric Oxide and Inflammation:
Molecular, Biochemical, and Clinical Aspects
A. Tomasi et al. (Eds.)
IOS Press, 2003

Alternative Functions of Mitochondria

Vladimir P. Skulachev
Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology,
Moscow State University, Moscow 119899, Russia
E-mail: [email protected]

Abstract: Mitochondria are known to be multifuctional intracellular organelles.

They carry out (i) energy conservation in forms of protonic potential and
ATP, (ii) thermoregulatory energy dissipation as heat, (iii) production of useful
substances, (iv) decomposition of harmful substances, and (v) regulation of
intracellular processes. It is suggested that mitochondria are equipped by a
mechanism of self-elimination ("mitoptosis") responsible for purification of
mitochondrial population from unwanted organelles (e.g., ROS-overproducing
mitochondria). Massive mitoptosis is assumed to induce apoptosis due to release of
the cell death proteins normally hidden in the intermembrane space of mitochondria.
In this way tissues are purified from ROS-overproducing and other unwanted cells.

1. Energy conservation

1.1 Phosphorylating respiration

The respiration-coupled energy conservation in form of ATP is usually the most important
mitochondrial function. In the aerobic cell, phosphorylating respiration is responsible, as a
rule, for production of 90-95 % of the total ATP amount, the rest being synthesized by
glycolytic phosphorylation. All the ATP synthesized from ADP and inorganic phosphate is
hydrolyzed back to ADP and phosphate to support the energy-consuming processes in the
same cell. The adult human forms and decomposes as much as about 40 kg ATP per day [1].
In mitochondria, more than 90 % of the respiratory phosphorylation is catalyzed by
the H+-ATP-synthase, an enzyme converting the respiratory chain-produced electro-
chemical H+ potential difference into ATP [1–4]. Very small (but sometimes
essential) portion of the respiratory energy is converted to GTP by succinate thiokinase [4].
Both respiratory chain enzymes (Complexes I, III and IV), catalyzing electron transfer from
NAD(P)H to 62, and H+-ATP-synthase are localized in the inner mitochondrial membrane.
The great majority of the formed ATP molecules is exported from mitochondria by the
ATP/ADP antiporter in exchange for extramitochondrial ADP (eqs. 1-3).
2 V.P. Skulachev /Alternative Functions of Mitochondria

ATP/ADP-antiporter
ADPout + ATPin ---------- > ADP,n + ATPout (3)

1.2 Non-phosphorylating energy-conserving respiration

The respiration-produced can be utilized by mitochondria not only to form ATP but
also to support some other energy-consuming processes namely reverse electron transfer in
the respiratory chain and uphill transport of certain solutes from cytosol to the
mitochondrial matrix.
Two reactions of the reverse electron transfer are of physiological significance. 1
mean (i) oxidation of succinate (redox potential, +0.03 V) by NAD + (redox potential, -0.32
V) and (ii) oxidation of NADH by NADPH responsible for maintenance of
[NADPH]/NADP+]>> [NADH]/[NAD+] in spite of the fact that redox potential of the
NADPH/NADH* pair is almost equal to that of NADH/NAD* pair. The former process
includes a reversal of NADH-CoQ reductase (Complex 1 of the respiratory chain). Usually
it operates as a generator catalysing the downhill electron transfer from NADH to
CoQ. However, when NAD+ is reduced by succinate, the same complex acts as a
consumer carrying out the uphill transfer of electrons from CoQHa to NAD+ [5].
Reduction of NADP+ by NADH is catalysed by H*-transhydrogenase, a
consumer competent in the H" transfer between two nicotinamide adenine nucleotide in a
-linked fashion. As a source of, respiration or ATP hydrolysis can be used [5],
The same energy sources are employed to create gradients of solutes between cytosol
and mitochondrial matrix. For instance, mitochondria accumulate Ca2* by means of
electrophoretic Ca2 uniporter.
ATP/ADP antiporter catalyzes transmembrane exchange of ADP3- for ATP4-. This
results in import of ADP and export of ATP at the expense of the respiration energy.

1.3 The long distance power transmission

Translated from Greek, the word "mitochondrion" means "thread-grain". This term was
introduced many years ago by cytologists who used the light microscope. The first students
of mitochondria always indicated that these organelles may exist in two basic forms:
(1) filamentous and (2) spherical or ellipsoid.
By applying the fluorescent cation method, it was revealed that a filamentous
mitochondria may represent an electrically united system operating as intracellular electric
cables. A local damage of such a filament by very narrow (0.5 in diameter) laser beam
was shown to cause efflux of the cation and, hence, the fluorescence decreases in the entire
50 mitochondrial filament in a human fibroblast cell.
Later the same approach was applied to study heart muscle mitochondria that
represent mainly spherical bodies. It was found that these organelles form electrically
conductive intermitochondrial contacts. As a result, heart mitochondria can be united to
clusters composed of tens spherical organelles (we coined them Streptio mitochondriale).
Both mitochondrial filaments and clusters were assumed to be used by the cell to transmit
inside the cell [4–6].

2. Energy dissipation

Almost all the energy conserved in form of ATP releases as heat when the ATP-dependent
functions of organism are performed. Thus, then the ambient temperature lowers, a man or
 V.P. Skulachev /Alternative Functions of Mitochondria 3

a warm-blooded animal can increase their functional activity and produce in this way
additional heat to keep constant the body temperature. This is the case when muscle
contractions are activated by the cold (so-called shivering thermogenesis). However, such a
mechanism is hardly optimal since here the main goal of thermoregulation (to make
physiological functions temperature-independent) is, in fact, not realized. Moreover,
shivering thermogenesis is rather complicated process requiring the H+-ATP-synthase-
produced ATP to be transported from mitochondria to cytosol and hydrolyzed by
actomyosin. Then the products (ADP and phosphate) should be transported in opposite
direction i.e. from cytosol to mitochondria. It is not surprising, therefore, that during cold
adaptation, the shivering thermogenesis is replaced by another mechanism which represents
much simpler way from respiration to heat and does not require the main (contractile)
function of muscle to be activated at cooling. The mechanism in question is
thermoregulatory uncoupling of respiration and phosphorylation.
Uncoupling results in dissipation of the respiratory chain-produced due to
increased H+ conductance of the inner mitochondrial membrane. Thus energy released by
respiration is immediately dissipated as heat without formation and hydrolysis of ATP.
Non-esterified fatty acids proved to be compounds mediating the thermoregulatory
uncoupling. They operate as protonophorous uncouplers with the help of special
uncoupling proteins (UCPs) or some mitochondrial antiporters i.e. the ATP/ADP antiporter
and aspartate/glutamate antiporter [1–5].

3. Synthesis of useful compounds

Both energy conservating and dissipating functions described above appear to be

alternative to the functions dealing with conversion of substances rather than energy.
Formally speaking, the respiration-linked substance interconversions might be carried out
by the same respiratory chain which is involved in the energy-linked functions. Sometimes
this really happens. However, if it were always the case, these functions would be tightly
coupled to the ATP synthesis and, hence, would be dependent upon the ADP availability.
Such a restriction is hardly desirable for the cell. This is why the metabolic functions of
respiration are catalyzed, at least in some cases, by non-coupled respiratory enzymes that
transfer electrons with no generated. For instance, some steps of the steroid hormone
syntheses in adrenal cortex mitochondria are mediated by special non-coupled respiratory
chain including a NADPH-oxidizing flavoprotein, the iron-sulphur protein adrenodoxin and
mitochondrial cytochrome P450. All of them are localized, like the energy-coupled
respiratory chain, in the inner mitochondrial membrane.
Biosyntheses of DNA, RNA and proteins in mitochondria can be another example of
constructive metabolic function of these organelles. It certainly requires ATP and therefore is
alternative to energy supply for extramitochondrial ATP-consuming processes [5].

4. Removal of unwanted compounds

Such a function may be exemplified by the urea synthesis from NHs. This ATP-consuming
process is localized in matrix of liver mitochondria. Like other intramitochondrial
biosyntheses, it is alternative to the ATP export from mitochondria to cytosol.
Oxidation of lactate after heavy muscle work seems to be another example of
mitochondrial function dealing with removal of a harmful compound responsible for
dangerous acidosis of the tissue. It was found that the ATP formation coupled to lactate
4 V.P. Skulachev /Alternative Functions of Mitochondria

oxidation by skeletal muscle mitochondria is smaller than that coupled to oxidation of any
other NADMinked substrate. This phenomenon was due to co-operation of non-coupled
and coupled respiratory chains.
Mitochondria can take part in antioxidant defence of the cell by maintaining low
intracellular oxygen concentration. In fact, this may be regarded as removal of an excess of
O2. Under resting conditions, this process seems to be carried out by partially uncoupled or
non-coupled respiration [5].

5. Mitochondria and reactive oxygen species

5.1 Mild uncoupling

Parallel with normal (enzymatic) four electron reduction of O2 to H2O by cytochrome

oxidase, non-enzymatic one electron reduction of O2 to superoxide (O2) takes place in
mitochondria. This "parasitic" chemical reaction appears to be inevitable since the initial
and middle steps of the respiratory chain contain very reactive electron carriers of negative
redox potential (e.g., chemically component in the one electron reduction of oxygen).
Besides non-enzymatic O2 generation, O2 can be enzymatically formed as a result
of the -consuming reverse electron transfer from succinate to O2. In fact, standard
redox potential of fumarate/succinate is slightly positive whereas that of O2/O2 is negative.
It was found that generated by succinate oxidation via Complexes III and IV can be
used to reduce O2 to O2 (eq. 4):

The process proved to be inhibited by even a small decrease ("mild

uncoupling") [5]. It was suggested that mild uncoupling is carried out by free fatty acids
operating as protonophores with the help of UCPs and ATP/ADP-antiporter [5].

5.2 Cytochrome c as an enzyme regenerating O2 from O2

Mild uncoupling seems to be a first line of the mitochondrial antioxidant defence which
prevents the O2 formation. If, nevertheless, some O2 is still formed, the next line of the
defence is actuated. This role can be performed by cytochrome c dissolved in the solution
occupying the intermembrane space of mitochondria. In fact, cytochrome c is competent in
oxidizing O2 back to O2
cyt. c3 + O2 cyt. c2+ + O2 (5)
3+ 2+
where cyt. c and cyt. c are for the oxidized and reduced cytochromes c, respectively.
Reduced cytochrome c formed by reaction (5) can then be oxidized by O2 via
cytochrome oxidase. In fact, the O2 oxidation by cytochrome c3+ represent the most
effective way to scavenge since O2 formed from O2 is converted back to 02. As for
the other reaction product, cyt. c2+, it can then be used to produce some in terminal
segment of the respiratory chain. We found, however, that the only the soluble, but not the
membrane-bound, cytochrome c is competent in superoxide oxidation. This means that
desorption of cytochrome c from the inner mitochondrial membrane can. in principle, be
 V.P. Skulachev /Alternative Functions of Mitochondria 5

regarded, besides an apoptosis-inducing events (see below, Section 8), also as activation of
an antioxidant system scavenging O2.

5.3 Other ROS scavengers

Besides cytochrome c, there are several other compounds operating as the ROS scavengers
but none of them can qualitatively convert O2 back to O2. Some scavengers are
irreversibly damaged when reacting with ROS, others can be regenerated from ROS-
oxidized form back to reduced form. For the water phase of the cell, reduced glutathione
and ascorbate are most important antioxidants whereas in membranes this function is
inherent, first of all, in tocopherol, carotenoids and CoQH2.
Important role is played by superoxide dismutase (SOD) converting the membrane-
impermeable superoxide anion (O2) to the membrane-permeable hydrogen peroxide
(H2O2). The latter can escape the cell to be diluted by extracellular medium. For unicellular
organisms, such a dilution is the final step of ROS detoxication. On the other hand, in
higher organisms hydrogen peroxide escaping the ROS-producing cell can be used an
alarm signal for its neighbours. Moreover, H2O2 is utilized inside the cell by glutathione
peroxidase. Oxidized glutathione formed is regenerated to the reduced glutathione by
glutathione reductase oxidizing NADPH. One more very important process of H2O2
removal is carried out by catalase which decomposes 2H2O2 to O2 and 2H2O [5].

5.4 Inhibition of aconitase by superoxide

Mitochondrial aconitase, enzyme catalyzing the first steps of the citric acid cycle, is known
to be reversibly inactivated by very low concentrations of O2 This should results in (i)
inhibition of supply of the respiratory chain by reducing equivalents and, hence, of the O2
formation, and (ii) accumulation of citrate, an excellent Fe2+ and Fe3+ chelator.
Autooxidable citrate3"-Fe2+ complex immediately reacts with O2. As a result, Fe2+ is
oxidized to Fe3+ , an effect preventing the production of OH', the most aggressive ROS,
which requires Fe2+ to be formed from H2O2 ("Fenton reaction"). The Fe3+ obtained
remains bound to citrate since its binding to citrate is much stronger than that of Fe2+ [5].
Interestingly, cytosolic aconitase was recently shown to function also as an iron
sensor. Earlier the cytosolic form of aconitase seemed to be an enzyme-"unemployed"
since the majority of other citric acid cycle enzymes are absent from cytosol. It was found,
however, that this enzyme plays a crucial role in regulating both the iron delivery to the cell
and iron storage [5].

6. Mitoptosis, programmed elimination of mitochondria

There is some indications that mitochondria possess a mechanism of self-elimination. This

function was ascribed to the so-called permeability transition pore (PTP). The PTP is a
rather large nonspecific channel located in the inner mitochondrial membrane. The PTP is
permeable for compounds of molecular mass < 1.5 kDa. The PTP is usually closed. A
current point of view is that PTP opening results from some modification and conformation
change of the ATP/ADP antiporter. Oxidation of Cys56 in the antiporter seems to convert it
to the PTP in a way that is catalyzed by another mitochondrial protein, cyclophilin. When
opened, the PTP makes impossible the performance of the main mitochondrial function,
i.e., coupling of respiration with ATP synthesis. This is due to the collapse of the
membrane potential and pH gradient across the inner mitochondrial membrane that mediate
respiratory phosphorylation. Membrane potential is also a driving force for import of
6 V. P. Skulachev / AIternative Functions of Mitochondria

cytoplasmic precursors of mitochondrial proteins. Moreover, it is strictly required for the

proper arrangement of mitochondrially-synthesized proteins in the inner membrane of the
mitochondrion. Thus, repair of the PTP-bearing mitochondrion ceases, and the organelle
perishes.
It is noteworthy that the above scheme of elimination of a mitochondrion does not
require any extramitochondrial proteins. It can be initiated by a signal originating from a
particular mitochondrion, such as reactive oxygen species (ROS) produced by the
mitochondrial respiratory chain. ROS seem to oxidize the crucial SH-group in the
ATP/ADP-antiporter, thereby actuating the elimination process. This is why one can
consider this effect as the programmed death of the mitochondrion (mitochondrial suicide).
For this event, I coined the word mitoptosis, by analogy with apoptosis, the programmed
death of the cell. I also suggested that the biological function of mitoptosis is the
purification of the intracellular population of mitochondria from those that became
dangerous for the cell because their ROS production exceeded their ROS scavenging
capacity. It seems very probable that antioxidant defense is not the only function of
mitoptosis. However, at least some alternative mitoptotic functions require ROS to be
formed as mediators of mitoptosis (for example, disappearance of mitochondria during the
maturation of the mammalian erythrocytes) [6–8].

7. Massive mitoptosis results in apoptosis

Opening of the PTP leads to an osmotic disbalance between the mitochondrial matrix and
cytosol, swelling of the matrix and, consequently, the loss of integrity of the outer
mitochondrial membrane, thus releasing the intermembrane proteins into the cytosol.
Among them, four proteins are of interest in this context: cytochrome c, apoptosis-inducing
factor (AIF), the second mitochondrial apoptosis-activating protein (Smac; also abbreviated
DIABLO), and procaspase 9. All these proteins are somehow involved in apoptosis.
In cytosol, cytochrome c combines with very high affinity with a cytosolic protein
called Apoptotic Protease-Activating Factor 1 (Apaf-1) and dATP. The complex, in turn,
combines with an inactive protease precursor, procaspase 9, to form the "apoptosome". As
a result, several procaspase 9 molecules are placed near each other, and they cleave each
other to form active caspases 9. When formed, caspase 9 attacks procaspase 3 and cleaves it
to form active caspase 3, a protease that hydrolyses certain enzymes occupying key
positions on the metabolic map. This causes cell death.
Considering these data, the following scenario of the final steps of the defense of a
tissue from mitochondrion-produced ROS seems to be most likely.
ROS induce PTP opening and, consequently, release of cytochrome c and other
proapoptotic proteins from mitochondria to the cytosol. If this occurs in a small fraction of
ROS-overproducing mitochondria, these mitochondria die. The cytosol concentrations of
proapoptotic proteins released from the dying mitochondria appear to be too low to induce
apoptosis. If, however, more and more mitochondria become ROS-overproduces, the
concentrations in question reach a level sufficient for the induction of apoptosis. This
results in purification of the tissue from the cells whose mitochondria produce too many
ROS.
In 1994, I postulated a scheme in which mitoptosis is an event preceding apoptosis
[9], In the same year, Newmeyer and coauthors published the first indication of a
requirement of mitochondria for apoptosis [10]. And quite recently, Tolkovsky and her
coworkers presented direct proof of the mitoptosis concept [11,12]. In the first set of
experiments, axotomized sympathetic neurons deprived of neuron grow factor were
studied. It was found that such neurons died within a few davs. showing cytochrome c
 V.P. Skulachev /Alternative Functions of Mitochondria 1

release and order typical features of apoptosis. However, the cells survive if a pan-caspase
inhibitor Boc-Asp (O-methyl)-CH2F (BAF) was added a day after the growth factor
deprivation. The cell survival was due to that the mitochondrion-linked apoptotic cascade
was interrupted downstream of the mitochondria. Electron microscopy showed that in such
cells all the mitochondria disappear within 3 days after the BAF addition. Later, the same
group reported that a similar effect could be shown using such classical experimental
models of apoptosis as HeLa cells treated with staurosporin. Again, addition of BAF to the
staurosporin-treated cells resulted in that (i) the cells lived longer and (ii) mitochondria
disappeared in the time scale of days. This was shown to be accompanied by disappearance
of mitochondrial DNA and as well as the cytochrome oxidase subunit IV encoded by
nuclear DNA. On the other hand, nuclear DNA, Golgi apparatus, endoplasmic reticulum,
centrioles, microtubules, and plasma membrane remained undamaged. Mitoptosis was
prevented by overexpression of antiapoptotic protein Bcl-2, which is known to affect
mitochondria upstream from the cytochrome c release.
Apparently, disappearance of mitochondria in the apoptotic cells without BAF could
not be seen since the cells die too fast to reveal mitoptosis and subsequent autophagia of
dead mitochondria. On the other hand, inhibition of apoptosis at a post-mitochondrial step
prevented fast death of the cells so there was time for mitoptosis to be completed [6,7].

References

[1] V.P. Skulachev, Membrane Bioenergetics, Springer, 1988.

[2] P. Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation, Biol. Rev. 41
(1966), 445-502.
[3] M. Saraste, Oxidative Phosphorylation at the fin de siecle. Science 283 (1999), 1488-1493.
[4] V.P. Skulachev, Energy transduction mechanisms (animals and plants). In: J.F. Hoffman and J.D.
Jamieson, eds., Handbook of Physiology, Amer. Physiol. Soc. Publ., New York, 1997, pp. 75–116.
[5] V.P. Skulachev, Mitochondrial physiology and pathology; concepts of programmed death of
organelles, cells and organisms. Mol. Asp. Med. 20 (1999), 139–184.
[6] V.P. Skulachev, Mitochondrial filaments and clusters as intracellular power-transmitting cables.
Trends Biochem. Sci. 26 (2001), 23–29.
[7] V.P. Skulachev, The programmed death phenomena, aging, and the Samurai law of biology. Exp.
Gerontol. 36 (2001), 995–1024.
[8] V.P. Skulachev, The programmed death phenomena: from organelle to organism. Ann. N.Y. Acad.
Sci. 959 (2002), 214–237.
[9] V.P. Skulachev, Lowering of intracellular O2 concentration as a special function of respiratory
systems of cells. Biochemistry (Moscow) 59 (1994), 1433-1434.
[10] D.D. Newmeyer, D.M. Farschon, and J.C. Reed, Cell-free apoptosis in Xenopus egg extracts:
inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochodria. Cell 79
(1994), 353-364.
[II] G.C. Fletcher, L. Xue, S.K. Passingham, and A.M. Tolkovsky, Death commitment point is advanced
by axotomy in sympathetic neurons. J. Cell Biol. 150 (2000), 741–754.
[12] L. Xue, G.C. Fletcher, and A.M.Tolkovsky, Mitochondria are selectively eliminated from eukaryotic
cells after blockade of caspases during apoptosis. Current Biol. 11 (2001), 361–365.
Other documents randomly have
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 Engineering - Student Handbook
Winter 2022 - Department

Prepared by: Assistant Prof. Smith

Date: July 28, 2025

Module 1: Experimental procedures and results

Learning Objective 1: Learning outcomes and objectives
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 2: Best practices and recommendations
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Learning Objective 3: Best practices and recommendations
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 4: Assessment criteria and rubrics
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 4: Diagram/Chart/Graph]
Learning Objective 5: Comparative analysis and synthesis
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 5: Diagram/Chart/Graph]
Example 5: Key terms and definitions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Important: Practical applications and examples
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 7: Diagram/Chart/Graph]
Definition: Comparative analysis and synthesis
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Study tips and learning strategies
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Theoretical framework and methodology
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Introduction 2: Experimental procedures and results
Definition: Interdisciplinary approaches
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Theoretical framework and methodology
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Key terms and definitions
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Key Concept: Statistical analysis and interpretation
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Practice Problem 14: Practical applications and examples
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 15: Diagram/Chart/Graph]
Note: Assessment criteria and rubrics
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Remember: Interdisciplinary approaches
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 17: Diagram/Chart/Graph]
Remember: Practical applications and examples
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 18: Diagram/Chart/Graph]
Definition: Practical applications and examples
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 19: Diagram/Chart/Graph]
Key Concept: Learning outcomes and objectives
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Section 3: Experimental procedures and results
Example 20: Best practices and recommendations
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Current trends and future directions
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 22: Diagram/Chart/Graph]
Example 22: Key terms and definitions
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 23: Theoretical framework and methodology
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 24: Practical applications and examples
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Experimental procedures and results
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Assessment criteria and rubrics
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 27: Study tips and learning strategies
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Case studies and real-world applications
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Problem-solving strategies and techniques
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Lesson 4: Key terms and definitions
Key Concept: Historical development and evolution
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Literature review and discussion
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 32: Diagram/Chart/Graph]
Key Concept: Study tips and learning strategies
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Interdisciplinary approaches
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Assessment criteria and rubrics
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Important: Theoretical framework and methodology
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Problem-solving strategies and techniques
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Definition: Interdisciplinary approaches
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 38: Diagram/Chart/Graph]
Definition: Comparative analysis and synthesis
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Important: Research findings and conclusions
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Section 5: Study tips and learning strategies
Practice Problem 40: Research findings and conclusions
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Theoretical framework and methodology
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Fundamental concepts and principles
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Important: Key terms and definitions
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Critical analysis and evaluation
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Practice Problem 45: Comparative analysis and synthesis
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 46: Interdisciplinary approaches
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 47: Theoretical framework and methodology
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Fundamental concepts and principles
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Case studies and real-world applications
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Unit 6: Experimental procedures and results
Key Concept: Learning outcomes and objectives
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 51: Assessment criteria and rubrics
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Comparative analysis and synthesis
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Best practices and recommendations
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 54: Diagram/Chart/Graph]
Remember: Learning outcomes and objectives
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 55: Literature review and discussion
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Key terms and definitions
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Fundamental concepts and principles
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Fundamental concepts and principles
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 59: Experimental procedures and results
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Test 7: Ethical considerations and implications
Remember: Problem-solving strategies and techniques
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 61: Diagram/Chart/Graph]
Note: Current trends and future directions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Practice Problem 62: Historical development and evolution
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Key terms and definitions
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 64: Diagram/Chart/Graph]
Important: Current trends and future directions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 65: Diagram/Chart/Graph]
Definition: Comparative analysis and synthesis
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 66: Interdisciplinary approaches
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Best practices and recommendations
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Problem-solving strategies and techniques
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Example 69: Interdisciplinary approaches
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Methodology 8: Learning outcomes and objectives
Example 70: Case studies and real-world applications
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Comparative analysis and synthesis
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 72: Diagram/Chart/Graph]
Remember: Best practices and recommendations
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 73: Learning outcomes and objectives
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 74: Diagram/Chart/Graph]
Example 74: Problem-solving strategies and techniques
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Research findings and conclusions
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 76: Problem-solving strategies and techniques
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Comparative analysis and synthesis
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Ethical considerations and implications
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Example 79: Case studies and real-world applications
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Abstract 9: Assessment criteria and rubrics
Important: Comparative analysis and synthesis
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Literature review and discussion
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Comparative analysis and synthesis
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Comparative analysis and synthesis
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 84: Diagram/Chart/Graph]
Important: Theoretical framework and methodology
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 85: Diagram/Chart/Graph]
Key Concept: Key terms and definitions
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Learning outcomes and objectives
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Historical development and evolution
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Key Concept: Interdisciplinary approaches
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
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