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Mitochondrial Permeability Transition in Stem Cells, Development, and Disease

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Cell Biology and Translational Medicine, Volume 18

Part of the book series: Advances in Experimental Medicine and Biology ((CBTMED,volume 1409))

Abstract

The mitochondrial permeability transition (mPT) is a process that permits rapid exchange of small molecules across the inner mitochondrial membrane (IMM) and thus plays a vital role in mitochondrial function and cellular signaling. Formation of the pore that mediates this flux is well-documented in injury and disease but its regulation has also emerged as critical to the fate of stem cells during embryonic development. The precise molecular composition of the mPTP has been enigmatic, with far more genetic studies eliminating molecular candidates than confirming them. Rigorous studies in the recent decade have implicated central involvement of the F1Fo ATP synthase, or complex V of the electron transport chain, and continue to confirm a regulatory role for Cyclophilin D (CypD), encoded by Ppif, in modulating the sensitivity of the pore to opening. A host of endogenous molecules have been shown to trigger flux characteristic of mPT, including positive regulators such as calcium ions, reactive oxygen species, inorganic phosphate, and fatty acids. Conductance of the pore has been described as low or high, and reversibility of pore opening appears to correspond with the relative abundance of negative regulators of mPT such as adenine nucleotides, hydrogen ion, and divalent cations that compete for calcium-binding sites in the mPTP. Current models suggest that distinct pores could be responsible for differing reversibility and conductance depending upon cellular context. Indeed, irreversible propagation of mPT inevitably leads to collapse of transmembrane potential, arrest of ATP synthesis, mitochondrial swelling, and cell death. Future studies should clarify ambiguities in mPTP structure and reveal new roles for mPT in dictating specialized cellular functions beyond cell survival that are tied to mitochondrial fitness including stem cell self-renewal and fate. The focus of this review is to describe contemporary models of the mPTP and highlight how pore activity impacts stem cells and development.

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Abbreviations

AHS:

Alpers-Huttenlocher Syndrome

ANT:

Adenine nucleotide translocator

CsA:

Cyclosporin A

CypD:

Cyclophilin D

ETC:

Electron transport chain

IMM:

Inner mitochondrial membrane

IMS:

Intermembrane space

MCUcx:

Mitochondrial calcium uniporter complex

mPT:

Mitochondrial permeability transition

mPTP:

Mitochondrial permeability transition pore

NIM811:

(Melle-4)cyclosporin

OMM:

Outer mitochondrial membrane

OSCP:

Oligomycin sensitive conferring protein subunit

OXPHOS:

Oxidative phosphorylation

Pi:

Inorganic phosphate

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TCA:

Tricarboxylic acid cycle

VDAC:

Voltage-dependent anion channel

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Acknowledgments

This work was supported by a grant from the National Institutes of Health (R01DK111599) to P.L.W.

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The authors declare explicitly that there are no conflicts of interest in connection with this article.

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S.P.D. wrote the manuscript, and P.L.W. wrote and revised the manuscript.

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  1. Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Sandeep P. Dumbali & Pamela L. Wenzel

  2. Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Pamela L. Wenzel

  3. Immunology Program, The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Pamela L. Wenzel

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  1. Sandeep P. Dumbali
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    Kursad Turksen

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Dumbali, S.P., Wenzel, P.L. (2022). Mitochondrial Permeability Transition in Stem Cells, Development, and Disease. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 18. Advances in Experimental Medicine and Biology(), vol 1409. Springer, Cham. https://doi.org/10.1007/5584_2022_720

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