Structural and biomechanical basis of mitochondrial movement in eukaryotic cells

Wan, Min; Kalyanasundaram, Aruna; Zhu, Jie

doi:10.2147/ijn.s52132

Cited by 21 publications

(17 citation statements)

References 61 publications

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“…Mitochondrial movement is essential to meet energy demands and prevent cell death [50], and is coordinated by different components of the cytoskeleton such as microtubules [51], which mediate directed movement of organelles [52]. Therefore, we sought to investigate the effect of directed vs. free movement on the behavior of the mitochondrial subpopulations.…”

Section: Resultsmentioning

confidence: 99%

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

et al. 2017

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Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity.

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Section: Resultsmentioning

confidence: 99%

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

et al. 2017

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“…Since Bim associates with the microtubule, it could be that Bim is important for stabilizing the cytoskeleton required for survival. Alteration in cytoskeleton integrity might affect mitochondrial respiration and apoptosis [ 177 ].…”

Section: Regulation Of Bim Expression and Activitymentioning

confidence: 99%

Regulation of Bim in Health and Disease

Sionov¹,

Vlahopoulos

Granot³

2015

Oncotarget

164

124

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The BH3-only Bim protein is a major determinant for initiating the intrinsic apoptotic pathway under both physiological and pathophysiological conditions. Tight regulation of its expression and activity at the transcriptional, translational and post-translational levels together with the induction of alternatively spliced isoforms with different pro-apoptotic potential, ensure timely activation of Bim. Under physiological conditions, Bim is essential for shaping immune responses where its absence promotes autoimmunity, while too early Bim induction eliminates cytotoxic T cells prematurely, resulting in chronic inflammation and tumor progression. Enhanced Bim induction in neurons causes neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Moreover, type I diabetes is promoted by genetically predisposed elevation of Bim in β-cells. On the contrary, cancer cells have developed mechanisms that suppress Bim expression necessary for tumor progression and metastasis. This review focuses on the intricate network regulating Bim activity and its involvement in physiological and pathophysiological processes.

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“…Fusion is the process by which mitochondria join together, whereas fission is the process that allows the separation of mitochondria [2]. Fission facilitates the distribution of mitochondria along cytoskeleton tracts, which provides energy throughout the cell [3], and helps to sequester damaged mitochondria and promote autophagy of these damaged organelles [4,5]. Mitochondrial fission is also required for apoptosis, where cells with excessive damage undergo programmed cell death [6,7].…”

Section: Introductionmentioning

confidence: 99%

The FtsZ Homolog, FszB, Inhibits Mitochondrial Dynamics in Dictyostelium discoideum

Vogel

Pittman

Naylor

2019

Cells

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Dictyostelium discoideum is a well-established mitochondrial model system for both disease and dynamics, yet we still do not understand the actual mechanism of mitochondrial dynamics in this system. The FtsZ proteins are known to mediate membrane remodeling events such as cytokinesis in bacteria and fission of chloroplasts; D. discoideum has two FtsZ proteins, FszA and FszB. To determine the role of these proteins in mitochondrial dynamics we overexpressed FszB-GFP and determined its effect on fission, fusion, and motility in the presence of intact and disrupted cytoskeletal filaments. Here we show that overexpression of FszB-GFP decreases mitochondrial dynamics and suggest that actin may play a positive role driving fission in the context of excessive inhibition by overexpressed FszB-GFP.

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Structural and biomechanical basis of mitochondrial movement in eukaryotic cells

Cited by 21 publications

References 61 publications

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

Regulation of Bim in Health and Disease

The FtsZ Homolog, FszB, Inhibits Mitochondrial Dynamics in Dictyostelium discoideum

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