pubmed.ncbi.nlm.nih.gov

Oxygen control of intracellular distribution of mitochondria in muscle fibers - PubMed

. 2013 Sep;110(9):2513-24.

doi: 10.1002/bit.24918. Epub 2013 Apr 30.

Affiliations

Oxygen control of intracellular distribution of mitochondria in muscle fibers

B Pathi et al. Biotechnol Bioeng. 2013 Sep.

Abstract

Mitochondrial density in skeletal muscle fibers is governed by the demand for aerobic ATP production, but the heterogeneous distribution of these mitochondria appears to be governed by constraints associated with oxygen diffusion. We propose that each muscle fiber has an optimal mitochondrial distribution at which it attains a near maximal rate of ATP consumption (RATPase ) while mitochondria are exposed to a minimal oxygen concentration, thus minimizing reactive oxygen species (ROS) production. We developed a coupled reaction-diffusion/cellular automata (CA) mathematical model of mitochondrial function and considered four fiber types in mouse extensor digitorum longus (EDL) and soleus (SOL) muscle. The developed mathematical model uses a reaction-diffusion analysis of metabolites including oxygen, ATP, ADP, phosphate, and phosphocreatine (PCr) involved in energy metabolism and mitochondrial function. A CA approach governing mitochondrial life cycles in response to the metabolic state of the fiber was superimposed and coupled to the reaction-diffusion approach. The model results show the sensitivity of important model outputs such as the RATPase , effectiveness factor (η) and average oxygen concentration available at each mitochondrion to local oxygen concentration in the fibers through variation in the CA model parameter θdet , which defines the sensitivity of mitochondrial death to the oxygen concentration. The predicted optimal mitochondrial distributions matched previous experimental findings. Deviations from this optimal distribution corresponding to higher CA model parameter values (a more uniform mitochondrial distribution) lead to lower aerobic rates. In contrast, distributions corresponding to lower CA model parameter values (a more asymmetric distribution) lead to an increased exposure of mitochondria to oxygen, usually without substantial increases in aerobic rates, which would presumably result in increased ROS production and thus increased risks of cytotoxicity.

Keywords: cellular automata; effectiveness factor; muscle; optimal mitochondrial distribution; reaction-diffusion model.

Copyright © 2013 Wiley Periodicals, Inc.

PubMed Disclaimer

Figures

Figure 1
Figure 1

Mitochondrial distribution patterns in EDL 2b fibers with boundary oxygen concentration of 35 μM. (A) Original distribution prior to CA iterations and redistributed mitochondria using CA rules to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F). Grid spaces containing mitochondria are represented in red.

Figure 2
Figure 2

Oxygen concentration profiles corresponding to mitochondrial distribution patterns in EDL 2b fibers shown in Fig. 1. prior to CA iterations (C) and after redistribution (D). Mitochondrial distribution patterns in EDL 2b fibers with boundary oxygen concentration of 35 μM. (A) Original distribution prior to CA iterations and redistributed mitochondria using CA rules to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F).

Figure 3
Figure 3

Non dimensionalized average concentrations of metabolites corresponding to mitochondrial distribution patterns in EDL 2b fibers shown in Fig. 1 with boundary oxygen concentration of 35 μM. Metabolite concentration corresponding to original distribution prior to CA iteration (A), Variation of non dimensionalized average concentration of metabolites with CA iterations to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F).

Figure 4
Figure 4

Oxygen concentration profiles corresponding to mitochondrial distribution patterns in EDL 2b fibers shown in Fig. 1 for redistributed mitochondria for θdet values of 0.15 (A), 0.35 (B), 0.55 (C), 0.75 (D) and 0.95 (E) with boundary oxygen concentration of 18 μM.

Figure 5
Figure 5

Mitochondrial distribution patterns in EDL 2x fibers with boundary oxygen concentration of 35 μM. (A) Original distribution prior to CA iterations and redistributed mitochondria using CA rules to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F). Grid spaces containing mitochondria are represented in red.

Figure 6
Figure 6

Mitochondrial distribution patterns in SOL 2a fibers with boundary oxygen concentration of 35 μM. (A) Original distribution prior to CA iterations and redistributed mitochondria using CA rules to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F). Grid spaces containing mitochondria are represented in red.

Figure 7
Figure 7

Mitochondrial distribution patterns in SOL 1 fibers with boundary oxygen concentration of 35 μM. (A) Original distribution prior to CA iterations and redistributed mitochondria using CA rules to reach a steady state for θdet values of 0.15 (B), 0.35 (C), 0.55 (D), 0.75 (E) and 0.95 (F). Grid spaces containing mitochondria are represented in red.

Figure 8
Figure 8

Model results showing RATPase, effectiveness factor (η) and average oxygen concentration per mitochondrion for EDL 2b (A, B and C) and EDL 2x (D, E and F) fibers for different values of MWr for both normoxic (i.e. 35.1 μM) and hypoxic (i.e. 18 μM) case.

Figure 9
Figure 9

Model results showing RATPase, effectiveness factor (η) and average oxygen concentration per mitochondrion for SOL 2a (A, B and C) and SOL 1 (D, E and F) fibers for different values of MWr for both normoxic (i.e. 35.1 μM) and hypoxic (i.e. 18 μM) case.

Similar articles

Cited by

References

    1. Amicarelli F, Ragnelli AM, Aimola P, Bonfigli A, Colafarina S, Di Ilio, Miranda M. Age-dependent ultrastructural alterations and biochemical response of rat skeletal muscle after hypoxic or hyperoxic treatments. Biochim Biophys Acta. 1999;1453:105–114. - PubMed
    1. Beard DA. A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation. PLOS Computational Biology. 2005;1(4):252– 264. - PMC - PubMed
    1. Booth FW, Holloszy JO. Cytochrome c turnover in rat skeletal muscles. J Biol Chem. 1977;252:416–419. - PubMed
    1. Boyle KL. Mitochondrial distribution and glycogen dynamics suggest diffusion constraints in muscle fibers of the blue crab, Callinectes sapidus. J Exp Zool A. 2003;297:1–16. - PubMed
    1. Chan DC. Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol. 2006;22:79–99. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources