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Molecular mechanisms and consequences of mitochondrial permeability transition

Nature Reviews Molecular Cell Biology volume 23, pages 266–285 (2022)Cite this article

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Abstract

Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes. In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. This lack of molecular data was a significant setback that prevented mechanistic insight into the mPTP, pharmacological targeting and the generation of informative animal models. In recent years, experimental evidence has highlighted mitochondrial F1Fo ATP synthase as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. Recently, the resolution of the F1Fo ATP synthase structure by cryogenic electron microscopy led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. This Review provides an up-to-date reference for the understanding of the mammalian mPTP and its cellular functions. We review current insights into the molecular mechanisms of mPT and validated observations — from studies in vivo or in artificial membranes — on mPTP activity and functions. We end with a discussion of the contribution of the mPTP to human disease. Throughout the Review, we highlight the multiple unanswered questions and, when applicable, we also provide alternative interpretations of the recent discoveries.

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Fig. 1: ATP synthase structure and mechanism of mPTP opening.
Fig. 2: Mitochondrial consequences of mPT.
Fig. 3: Cellular roles of mPT.
Fig. 4: Pathological consequences of mitochondrial permeability transition.

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Acknowledgements

The Signal Transduction Laboratory is supported by the Italian Association for Cancer Research (IG-23670 to P.P. and IG-19803 to C.G.), A-ROSE, Progetti di Rilevante Interesse Nazionale (PRIN2017E5L5P3 to P.P and PRIN20177E9EPY to C.G.), the Italian Ministry of Health (GR-2013-02356747 to C.G.), the European Research Council (853057-InflaPML to C.G.) and local funds from the University of Ferrara to M.B., C.G. and P.P. P.P. is grateful to C. degli Scrovegni for her continuous support.

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  1. These authors contributed equally: Massimo Bonora, Carlotta Giorgi.

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  1. Department of Medical Sciences, Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy

    Massimo Bonora, Carlotta Giorgi & Paolo Pinton

  2. Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy

    Paolo Pinton

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Glossary

Voltage-dependent anion channel

(VDAC). A pore-forming protein of the outer mitochondrial membrane which allows the exchange of metabolites and ions.

Cyclosporine A

(CsA). A cyclic polypeptide able to bind and inhibit cyclophilins, including the mitochondrial permeability transition pore regulator cyclophilin D (CypD).

Adenine nucleotide translocator

(ANT). An integral membrane protein that exchanges ATP for ADP across the inner mitochondrial membrane.

Mitochondrial inorganic phosphate carrier

(PiC). An integral carrier solute that delivers phosphate across the inner mitochondrial membrane.

c-ring

A portion of the ATP synthase rotor (composed of an octamer of subunit c) responsible for the coupling of proton transport across the inner mitochondrial membrane to a rotative movement required for catalysis.

Cristae

Foldings of the inner membrane that create specialized compartments required to optimize mitochondrial functions.

Cyclophilin D

(CypD). A peptidyl-prolyl cis–trans isomerase located in the mitochondrial matrix. By binding to mitochondrial ATP synthase, it functions as a positive regulator of mitochondrial permeability transition pore (mPTP) opening and the target of the mPTP inhibitor cyclosporine A (CsA).

Mitoplasts

Mitochondria artificially deprived of the outer mitochondrial membrane.

Mitochondrial membrane potential

The electric potential generated across inner mitochondrial membrane by the proton pumping activity of respiratory complexes.

BCL-2 family

A group of evolutionarily conserved proteins that harbour a BCL-2 homology domain. Mostly known for their regulatory role in regulated cell death, mostly apoptosis.

Sirtuin

Member of a family of NAD-dependent protein deacetylases or (ADP-ribosyl)transferases able to respond to nutrient stress, potentiating mitochondrial biogenesis and activity.

ERK-mediated signalling

A signal transduction pathway regulating cellular processes that includes proliferation, differentiation, apoptosis and stress responses, having a major impact in tumour development.

Respiratory chain

A group of multimeric protein complexes in the inner mitochondrial membrane, carrying mitochondrial respiration.

Necrosis

A form of poorly regulated cell death characterized by energetic crisis and its consequent chaotic disruption of intracellular structures.

Mitophagy

The selective degradation of a mitochondrion via the lysosomal machinery.

PINK1–parkin system

A kinase/ubiquitinase system required for the tagging of outer mitochondrial membrane proteins, which in turn label mitochondria to be cleared via lysosomal degradation.

Damage-associated molecular pattern

A molecule released from a damaged or diseased cell able to stimulate a sterile immune or inflammatory response.

Inflammasome

A group of intracellular multimeric protein complexes that activate inflammatory caspase 1.

Amyotrophic lateral sclerosis

A progressive neurological disease that primarily affects the neurons responsible for controlling voluntary muscle movement.

Ischaemia

The deficient supply of blood to a tissue due to obstruction of the inflow of arterial blood.

Reperfusion injury

Type of tissue damage that is caused by the restoration of blood supply after a prolonged period of ischaemia.

Necroptosis

A form of regulated cell death initiated by death receptors and dependent on RIPK1, RIPK3 and MLKL.

Ullrich congenital muscular dystrophy

A rare hereditary muscle condition characterized by abnormalities in collagen type VI, resulting in impaired progressive muscle weakness.

Free radical theory of ageing

A theory of ageing proposing that organisms age because they accumulate oxidative damage.

NAD+

A molecule that carries reduced equivalents between enzymes to run redox reactions. Decline in its level is associated with ageing and ageing-related mitochondrial dysfunction.

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Bonora, M., Giorgi, C. & Pinton, P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol 23, 266–285 (2022). https://doi.org/10.1038/s41580-021-00433-y

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