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Messoud Efendiev

Mathematical
Modeling of
Mitochondrial
Swelling
Mathematical Modeling of Mitochondrial Swelling
Messoud Efendiev

Mathematical Modeling
of Mitochondrial Swelling

123
Messoud Efendiev
Institute of Computational Biology
Helmholtz Center Munich
Neuherberg, Germany

ISBN 978-3-319-99099-6 ISBN 978-3-319-99100-9 (eBook)

https://doi.org/10.1007/978-3-319-99100-9

Library of Congress Control Number: 2018953717

Mathematics Subject Classification (2010): 35B40, 35K45, 37N25

© Springer Nature Switzerland AG 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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“Mieux vaut une tête bien faite qu’une tête
bien pleine”
“Better a well-made mind than
a well-filled mind”
(Michel Montaigne)
Of course, very few people today enjoy
both, and they are therefore exceptional,
and very important for mankind. One
of the people whom I have met in my life who
has both completely is Sadik Murtuzayev.
This book is dedicated to him with admiration
on the occasion of his 90th birthday.
Preface

In this book, new mathematical models of mitochondria swelling are presented

which take into account, in particular, spatial effects. Depending on the mod-
els under considerations, the problem consists of either one reaction diffusion
(including degenerate diffusion) equation coupled with a system of three ordinary
differential equations (ODEs), describing the evolution in time of three subpop-
ulations of mitochondria, or of four coupled partial differential equations (PDEs)
between calcium concentration and subpopulations of mitochondria.
The models in the book are of the form

Bt u = d1 A(u) + d2 g(u)N2 ,
Bt N1 = d3 x N1 ´ f (u)N1 ,
Bt N2 = d4 x N2 + f (u)N1 ´ g(u)N2 ,
Bt N3 = d5 x N3 + g(u)N2 .

where the coefficients d1 , d2 are positive constants, while d3 , d4 , and d5 are non-
negative constants and f and g are given functions, describing the transition from
unswollen N1 (x, t) to swollen N2 (x, t) and from swollen N2 (x, t) to completely
swollen N3 (x, t) mitochondria.
The boundary conditions vary for the type of the model and can be generally
formulated as a(x)u + b(x)Bν u = h(x) on the boundary of , reflecting the
swelling of mitochondria scenarios in vitro and in vivo, where a, b, h are given real
functions that are defined on the boundary of  and Bν u is the normal derivative
at the boundary. As mentioned above the novelty in this book compared with
existing mitochondria models is that it takes into account spatial effects by means
of the diffusion operator A both with and without spatial diffusion for mitochondria
subpopulations. In the book, we consider both the nondegenerate diffusion A(u) =
x u, where x is the standard Laplacian, and the degenerate case A(u) = x um
with m ą 1.

vii
viii Preface

Here  is a bounded domain in Rn , which will be, depending on the model,

either the test tube (in vitro) or the whole cell (in vivo).
We especially emphasize that the new approach developed in this book is capable
of modeling each of the in vitro, in silico, and in vivo cases. The cases vary with
respect to the initial and boundary conditions dependent on the choice of the domain
as either the test tube or the whole cell.
The book consists of seven chapters. Chapter 1 is of an introductory character
and includes four subsections. In Sect. 1.1, we give very briefly the definitions of
Sobolev spaces and we state the embedding theorems. Section 1.2 is devoted to the
generalization of Poincare inequalities. In Sects. 1.3 and 1.4, we give the properties
of Nemytski operators and the subdifferential in Hilbert spaces respectively which
play a crucial role in our analysis of the mitochondria models.
Chapter 2 deals with the biological background of mitochondria swelling and its
role in the apoptosis scenario.
In Chap. 3, we study a model of the description of mitochondria swelling based
on experimental observations. Chapter 3 consists of four subsections: Sect. 3.1 is
devoted to existing models that are focused on the evolution in time of mitochondria
and, as a consequence, are described by ordinary differential equations (ODE
models); they do not take into account local effects and only work with mean
values over the whole domain. Coming from an ODE model, it is natural to
think about the necessity of including spatial effects by means of considering
partial differential equations (PDE models). We consider spatial effects in Sect. 3.2.
Moreover, we show in Sect. 3.2 that how to take into account this spatial effect
is dictated by experiments. Indeed, in this section it is shown that the same
amount of mitochondria with different concentrations has an influence on the
volume outcome, that is, leads to different mitochondria swelling scenarios. With
the necessity of taking into account spatial effects, in Sect. 3.3 we deal with the
mitochondria model in vitro. We assume that mitochondria in the test tube as well
as within the cell do not move in any direction, and hence, the spatial effects are
only introduced by the calcium evolution. As a consequence of this assumption,
our mathematical model of mitochondria swelling is described by PDE-ODE
systems (the so-called PDE-ODE coupling) with Neumann boundary conditions.
We emphasize that in this vitro model we choose the underlying domain to be the
test tube.
Chapter 4 is devoted to the mathematical analysis of the model obtained in
Sect. 3.3 and consists of four subsections. In Sect. 4.1, we verify the obtained
model and prove the well posedness of the PDE-ODE systems corresponding
to it. Having ordinary differential equations describing the evolution in time of
three subpopulations of mitochondria indicates that we assume the mitochondria
in the test tube, as well as within cells, do not move in any direction and hence
the spatial effects are only introduced by the calcium evolution obeying a partial
differential equation (PDE), namely a reaction-diffusion equation. In Sect. 4.2,
we study the long-time dynamics of solutions of the PDE-ODE coupling. We
obtain the complete classifications of the limiting profile of solutions and study
partial and complete classification scenarios depending on the given data. Note
Preface ix

that these scenarios, namely, partial and complete swelling scenarios, have been
observed in experiments. Section 4.3 deals with the numerical simulation (in
silico) of PDE-ODE systems. One of the remarkable results here is the clearly
visible spreading calcium wave. If we compare the dynamics with those of simple
diffusion without any positive feedback, the numerical results show that the resulting
calcium evolution induced by mitochondria swelling is indeed completely different.
Our numerical simulations show that a small change in the initial distribution
of calcium is enough to shift the behavior from partial to complete swelling
behavior. In Sect. 4.4, we continue our analysis of a coupled PDE-ODE model
of calcium-induced mitochondria swelling in vitro. More precisely, we study
the long-time dynamics of solutions of PDE-ODE systems under homogeneous
Dirichlet boundary conditions. Note that, biologically, this kind of boundary
condition appears if we put some chemical material on the test-tube wall that
binds calcium ions and hence removes it as a swelling inducer. We especially
emphasize that the analytical machinery that was developed in Sect. 4.1 is not
applicable under homogeneous Dirichlet boundary conditions and therefore must
be extended. In this section, we show that the calcium ion concentration will tend
to zero and that, in general, complete swelling will not occur as time goes to
infinity. This distinguishes the situation under Dirichlet boundary conditions from
the situation under Neumann boundary conditions that were analyzed in Sect. 4.1.
In Sect. 4.5, we carry out numerical simulations validating the analytical results of
Sect. 4.4.
Chapter 5 deals with the swelling process in a living organism, so that in this
case we do not have a controlled environment as we had in the test tube. Here there
are three main factors that differ a great deal from the in vitro case, which was
considered in Chap. 3, that is:
1. Mitochondria are not uniformly distributed.
2. The induced calcium source is very localized.
3. The cell is not a closed system.
Chapter 5 consists of two subsections. In Sect. 5.4, we formulate mitochondria
swelling scenario in vivo as a PDE-ODE system with Robin boundary conditions,
which in turn reflects the fact that calcium ions can enter and leave the cell across
the permeable membrane. In this section, we prove the well posedness and study
large-time asymptotics of solutions of the corresponding initial boundary value
PDE-ODE problem. Moreover, in Sect. 5.4 it is shown that partial and complete
swelling behavior in vivo depends on the balance of concentration as well as on
the threshold parameter of initiation for swelling. In Sect. 5.5, we illustrate the
results of Sect. 5.4 with numerical simulations. Note that in the previous chapters
mathematical modeling of swelling of mitochondria and their analysis in vitro, in
vivo, and in silico were governed by the concept of standard diffusion for calcium
concentrations. The use of the standard Laplacian to describe diffusion processes
is generally accepted for mathematical idealization and indeed can explain some
aspects of mitochondria swelling scenarios observed in experiments. However,
from the viewpoint of applications it is also desirable to analyze the effect of
x Preface

degenerate diffusion, because there is no species which can diffuse infinitely fast
(a property of the standard diffusion). Therefore in Chap. 6, which consists of
two subsections, we consider the effect of degenerate diffusion on mitochondria
swelling behavior. In Sect. 6.1, we study the well posedness of solutions under
homogeneous Dirichlet boundary conditions. Note that we cannot apply the meth-
ods developed in previous chapters for nondegenerate diffusion and new methods
have been developed in order to study both well posedness and asymptotic behavior
of solutions. In this section, we show that the calcium ion concentration will
tend to zero and that, in general, complete swelling will not take place as time
goes to infinity in the case of degenerate diffusion. Section 6.2 gives numerical
simulations.
Note that in Chaps. 1–6 we essentially used the assumption that mitochondria
do not diffuse within the cell, which in turn led to ordinary differential equations
for the evolution of mitochondria subpopulations Ni , i = 1, 2, 3, as a result
of PDE-ODE coupling between calcium concentration and subpopulations of
mitochondria. However, there are indications that mitochondria do move under
certain circumstances in the test tube as well as within the cell in any direction,
e.g., dependent on the cell cycle, which in turn leads to partial differential equations
for mitochondria subpopulations Ni (x, t).
Chapter 7 consists of three sections. In Sect. 7.1, we systematically study this
PDE-PDE case as for the well posedness, dependence of solutions from boundary
conditions (in vitro and in vivo cases). In Sect. 7.2, we study asymptotic behavior of
solutions as for the partial and complete swelling scenarios. Section 7.3 verifies the
obtained results numerically.
Note that the development and study of mathematical models that take into
account spatial effects for the swelling of mitochondria was initiated by myself
in the interdisciplinary seminar at the Helmholtz Center of Munich and was
deepened afterward by the numerous, intensive, and stimulating discussions with
my colleagues Dr. H. Zischka and Dr. S. Schulz from the Institute of Toxicology
and Pharmacology at the Helmholtz Center of Munich.
I emphasize that the mathematical analysis of the obtained model was first carried
out in collaboration with my Ph.D. student S. Eisenhofer, where, in particular,
several challenging and open questions were formulated that must be answered in
order to shed light on and gain a deeper understanding of mitochondria swelling
scenarios in vitro, in vivo, and in silico. Together with my frequent coauthors and
friends, that is, with Prof. M. Otani (Japan) and Prof. H. Eberl (Canada), during
the last few years we systematically studied many of these challenging and open
questions. Therefore, I express my sincere thanks to all of my colleagues and friends
mentioned above, because without such stimulating and inspiring discussions and
joint works this book would not be possible.
I also thank the many friends and colleagues who gave me suggestions, advice,
and support. In particular, I wish to thank professors J.R.L. Webb, J. Wu, F. Hamel,
Y. Nishiura, M. Sörensen, and M. Pedersen.
Preface xi

Furthermore, I am greatly indebted to my colleagues at the Helmholtz Zentrum

München and Technische Universität München, the Alexander von Humboldt Foun-
dation, as well as Springer Publisher for their efficient handling of the publications.
Last but not least, I wish to thank my family for continuously encouraging me
during the writing of this book.

Neuherberg, Germany Messoud Efendiev

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