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The cell biology of mitochondrial membrane dynamics

Abstract

Owing to their ability to efficiently generate ATP required to sustain normal cell function, mitochondria are often considered the ‘powerhouses of the cell’. However, our understanding of the role of mitochondria in cell biology recently expanded when we recognized that they are key platforms for a plethora of cell signalling cascades. This functional versatility is tightly coupled to constant reshaping of the cellular mitochondrial network in a series of processes, collectively referred to as mitochondrial membrane dynamics and involving organelle fusion and fission (division) as well as ultrastructural remodelling of the membrane. Accordingly, mitochondrial dynamics influence and often orchestrate not only metabolism but also complex cell signalling events, such as those involved in regulating cell pluripotency, division, differentiation, senescence and death. Reciprocally, mitochondrial membrane dynamics are extensively regulated by post-translational modifications of its machinery and by the formation of membrane contact sites between mitochondria and other organelles, both of which have the capacity to integrate inputs from various pathways. Here, we discuss mitochondrial membrane dynamics and their regulation and describe how bioenergetics and cellular signalling are linked to these dynamic changes of mitochondrial morphology.

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Fig. 1: Mitochondrial structure and function.
Fig. 2: The mitochondrial life cycle involving fusion and fission.
Fig. 3: Changes in mitochondrial morphology impact on complex cellular processes/behaviours.

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Acknowledgements

Research in the L.S. laboratory is supported by AIRC IG19991, Italian Ministry of Education, University and Research PRIN 2017BF3PXZ, Fondation Leducq TNE15004, Muscular Dystrophy Association RG 603731 and Cariparo Foundation SIGMI. Research in the M.G. laboratory is supported by CARIPARO Starting Grant 2016 AIFbiol and Unipd STARS Consolidator FIRMESs.

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M.G. and L.S. conceptualized, wrote most of and edited the article. A.P. and C.G. wrote subsections. All authors approved the final content.

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Correspondence to Luca Scorrano.

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Glossary

Krebs cycle

A series of chemical reactions catalysed by enzymes that, on oxidation of the acetyl portion of acetyl coenzyme A, generate reducing equivalents (NADH and FADH2).

Membrane contact sites

Points at which two biological membranes run in parallel, at a constant distance, for several nanometres.

Oxidative phosphorylation

(OXPHOS). A process involving coupling between mitochondrial respiration and ATP production.

Mitochondrial respiratory chain

An ensemble of protein complexes whose coordinated activity catalyses the oxidation of reducing equivalents using oxygen as a terminal electron acceptor.

F1Fo-ATP synthase

Protein complex located at the inner mitochondrial membrane which mediates Pi addition to ADP to generate ATP in a process driven by the passage of protons.

Reducing equivalents

Electron donors in a redox reaction, which become oxidized. In mitochondria, NADH and FADH2.

BCL-2 family

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

Nucleoids

The literal meaning of this term is ‘nucleus-like’; it refers to a cluster of proteins and mitochondrial DNA, not surrounded by a membrane.

Bin/amphiphysin/Rvs (BAR) domain

Domains that mediate protein dimerization, first discovered in three protein classes named Bin, amphiphysin and Rvs (BAR).

Rhomboid protease

Intramembrane serine proteases that share a common catalytic domain composed of six membrane-spanning segments.

Iron–sulphur clusters

Metal prosthetic groups synthesized in mitochondria and acting as cofactors to catalyse several redox enzymatic activities.

Transferrin

An iron-binding glycoprotein that controls the level of free iron in the blood.

β-Oxidation

The catabolic process through which fatty acids are degraded in mitochondria to produce acetyl coenzyme A.

Ceramide

A family of lipid molecules composed of a fatty acid conjugated to the 18-carbon amino alcohol sphingosine.

Ischaemia–reperfusion injury

Tissue damage occurring especially in the heart on coronary artery occlusion and reperfusion on physicians’ intervention, for example, by percutaneous coronary intervention (formerly known as angioplasty with stent).

Omegasomes

Omega-shaped organelles which precede the formation of autophagosomes.

Retromer complex

A coat-like complex that mediates the recycling of the endosomal cargo into vesicles moving back to the Golgi apparatus.

5′-AMP-activated protein kinase

(AMPK). A key protein kinase that plays a critical role in cellular homeostasis. By phosphorylating a plethora of targets, it acts as a general switch to regulate cellular functions such as glucose absorption, fat oxidation and mitochondrial biogenesis.

Chemiosmotic theory

The theory proposed by Mitchell explaining ATP synthesis by mitochondria. The chemical energy of NADH and FADH2 is converted by the electron-transport chain into an electrochemical proton gradient across the inner mitochondrial membrane (IMM), whose free energy is in turn used to catalyse the phosphorylation of ADP by the IMM-bound ATP synthase.

Respiratory chain supercomplexes

Assembly of distinct respiratory chain complexes that guarantees efficient ATP production while reducing electron loss and production of reactive oxygen species.

Epithelial–mesenchymal transition

The process through which epithelial cells lose their characteristics of adhesion and polarity and acquire those typical of mesenchymal stem cells, including differentiation abilities

Nuclear factor of activated T cells

(NFAT). A family of transcription factors that can translocate into the nucleus in response to stimuli that enhance intracellular Ca2+ levels. Once in the nucleus, they induce transcription of target genes.

Naive embryonic stem cells

Embryonic stem cells of the preimplantation blastocyst that have the potential to generate all the somatic cell lineages.

Primed embryonic stem cells

Embryonic stem cells (from post-implantation epiblast) that can self-renew and differentiate.

Senescence-associated secretory phenotype

The release of factors such as inflammatory cytokines, growth factors and proteases from senescent cells.

Integrated stress response

A generally prosurvival stress response induced on exposure of the cell to either internal factors such as accumulation of unfolded protein leading to endoplasmic reticulum stress or external factors such as nutrient deprivation and viral infection.

ATF4

Cyclic AMP-dependent transcription factor 4 plays a key role in cell response to stress stimuli, mostly by promoting cell survival.

Mitokine

A cytokine produced by tissues undergoing mitochondrial stress and affecting other cell types in an endocrine or a paracrine manner. Mitokines include, for example, FGF21 and GDF15.

Leptin

This term derives from Greek leptos (‘thin’); it refers to a hormone that inhibits hunger.

Pro-opiomelanocortin (POMC) neurons

Neurons located in the arcuate nucleus within the hypothalamus; they produce a polypeptide named pro-opiomelanocortin, whose proteolysis generates several peptide hormones (including α-melanocyte-stimulating hormone and adrenocorticotropic hormone).

ER stress

A set of intracellular pathways activated by the cell to cope with abnormal accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER).

Brown adipocytes

Cells that compose the brown adipose tissue, enriched in mitochondria and characterized by high thermogenic potential.

Alveolar type 2 epithelial cells

One of the two cell types that build the alveolar epithelium, responsible for surfactant synthesis and secretion.

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Giacomello, M., Pyakurel, A., Glytsou, C. et al. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol 21, 204–224 (2020). https://doi.org/10.1038/s41580-020-0210-7

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