bims-mitdyn 2024-02-18 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2024–02–18
sixteen papers selected by
Edmond Chan, Queen’s University, School of Medicine

The HRI branch of the integrated stress response selectively triggers mitophagy.
Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
SLC25A39 links mitochondrial GSH sensing with iron metabolism.
A system for inducible mitochondria-specific protein degradation in vivo.
Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.
COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.
Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
Supralinear Dependence of the IP3 Receptor-to-Mitochondria Local Ca2+ Transfer on the Endoplasmic Reticulum Ca2+ Loading.
Mitochondrial Calcium Transport During Autophagy Initiation.
A KDELR-mediated ER-retrieval system modulates mitochondrial functions via the unfolded protein response in fission yeast.
Did mitophagy follow the origin of mitochondria?

Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]

The HRI branch of the integrated stress response selectively triggers mitophagy.

Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.

  To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.

Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control

DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
Nat Struct Mol Biol. 2024 Feb 12.

Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.

R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.

Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.

DOI: https://doi.org/10.1038/s41594-024-01225-6
Nat Commun. 2024 Feb 13. 15(1): 1328

Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

DOI: https://doi.org/10.1038/s41467-024-45524-4
Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738

Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.

Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.

  Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.

Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence

DOI:  https://doi.org/10.1016/j.celrep.2024.113738
Mol Cell. 2024 Feb 15. pii: S1097-2765(23)01083-3. [Epub ahead of print]84(4): 616-618

SLC25A39 links mitochondrial GSH sensing with iron metabolism.

Xiong Chen, Boyi Gan.

Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.

DOI: https://doi.org/10.1016/j.molcel.2023.12.037
Nat Commun. 2024 Feb 16. 15(1): 1454

A system for inducible mitochondria-specific protein degradation in vivo.

Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.

Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.

DOI: https://doi.org/10.1038/s41467-024-45819-6
Nat Commun. 2024 Feb 10. 15(1): 1252

Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.

Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.

Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.

DOI: https://doi.org/10.1038/s41467-024-45651-y
Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]

SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.

Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.

  SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.

Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
Nat Metab. 2024 Feb 13.

Selenium reduction of ubiquinone via SQOR suppresses ferroptosis.

Namgyu Lee, Sung Jin Park, Mike Lange, Tenzin Tseyang, Mihir B Doshi, Tae Yong Kim, Yoseb Song, Dong In Kim, Paul L Greer, James A Olzmann, Jessica B Spinelli, Dohoon Kim.

The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here we demonstrate that, via its metabolic intermediate hydrogen selenide, selenium reduces ubiquinone in the mitochondria through catalysis by sulfide quinone oxidoreductase. Through this mechanism, selenium rapidly protects against lipid peroxidation and ferroptosis in a timescale that precedes selenoprotein production, doing so even when selenoprotein production has been eliminated. Our findings identify a regulatory mechanism against ferroptosis that implicates sulfide quinone oxidoreductase and expands our understanding of selenium in biology.

DOI: https://doi.org/10.1038/s42255-024-00974-4
Mol Cell. 2024 Jan 24. pii: S1097-2765(24)00004-2. [Epub ahead of print]

COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.

Ludovic Pelosi, Laura Morbiato, Arthur Burgardt, Fiorella Tonello, Abigail K Bartlett, Rachel M Guerra, Katayoun Kazemzadeh Ferizhendi, Maria Andrea Desbats, Bérengère Rascalou, Marco Marchi, Luis Vázquez-Fonseca, Caterina Agosto, Giuseppe Zanotti, Morgane Roger-Margueritat, María Alcázar-Fabra, Laura García-Corzo, Ana Sánchez-Cuesta, Plácido Navas, Gloria Brea-Calvo, Eva Trevisson, Volker F Wendisch, David J Pagliarini, Leonardo Salviati, Fabien Pierrel.

  Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.

Keywords:  COQ4; Corynebacterium; coenzyme Q; coenzyme Q biosynthesis; coenzyme Q deficiency; mitochondria; oxidative decarboxylation; respiratory chain

DOI:  https://doi.org/10.1016/j.molcel.2024.01.003
Aging Cell. 2024 Feb 15. e14103

Mitochondrial S-adenosylmethionine deficiency induces mitochondrial unfolded protein response and extends lifespan in Caenorhabditis elegans.

Tse Yu Chen, Feng-Yung Wang, Pin-Jung Lee, Ao-Lin Hsu, Tsui-Ting Ching.

  S-adenosylmethionine (SAM), generated from methionine and ATP by S-adenosyl methionine synthetase (SAMS), is the universal methyl group donor required for numerous cellular methylation reactions. In Caenorhabditis elegans, silencing sams-1, the major isoform of SAMS, genetically or via dietary restriction induces a robust mitochondrial unfolded protein response (UPRmt ) and lifespan extension. In this study, we found that depleting SAMS-1 markedly decreases mitochondrial SAM levels. Moreover, RNAi knockdown of SLC-25A26, a carrier protein responsible for transporting SAM from the cytoplasm into the mitochondria, significantly lowers the mitochondrial SAM levels and activates UPRmt , suggesting that the UPRmt induced by sams-1 mutations might result from disrupted mitochondrial SAM homeostasis. Through a genetic screen, we then identified a putative mitochondrial tRNA methyltransferase TRMT-10C.2 as a major downstream effector of SAMS-1 to regulate UPRmt and longevity. As disruption of mitochondrial tRNA methylation likely leads to impaired mitochondrial tRNA maturation and consequently reduced mitochondrial translation, our findings suggest that depleting mitochondrial SAM level might trigger UPRmt via attenuating protein translation in the mitochondria. Together, this study has revealed a potential mechanism by which SAMS-1 regulates UPRmt and longevity.

Keywords:  S-adenosyl methionine; UPRmt; longevity; mitochondrial tRNA methyltransferase

DOI:  https://doi.org/10.1111/acel.14103
FEBS J. 2024 Feb 16.

Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.

Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.

  Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.

Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1111/febs.17083
Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241229273

Supralinear Dependence of the IP3 Receptor-to-Mitochondria Local Ca2+ Transfer on the Endoplasmic Reticulum Ca2+ Loading.

György Csordás, David Weaver, Péter Várnai, György Hajnóczky.

  Calcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. Ca2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP3) receptors (IP3R) can locally expose the mitochondrial Ca2+ uniporter (mtCU) to high [Ca2+] nanodomains. The Ca2+ loading state of the ER (Ca2 + ER) can vary broadly in physiological and pathological scenarios, however, the correlation between Ca2 + ER and the local Ca2+ transfer is unclear. Here, we studied IP3-induced Ca2+ transfer to mitochondria at different Ca2 + ER in intact and permeabilized RBL-2H3 cells via fluorescence measurements of cytoplasmic [Ca2+] ([Ca2+]c) and mitochondrial matrix [Ca2+] ([Ca2+]m). Preincubation of intact cells in high versus low extracellular [Ca2+] caused disproportionally greater increase in [Ca2+]m than [Ca2+]c responses to IP3-mobilizing agonist. Increasing Ca2 + ER by small Ca2+ boluses in suspensions of permeabilized cells supralinearly enhanced the mitochondrial Ca2+ uptake from IP3-induced Ca2+ release. The IP3-induced local [Ca2+] spikes exposing the mitochondrial surface measured using a genetically targeted sensor appeared to linearly correlate with Ca2 + ER, indicating that amplification happened in the mitochondria. Indeed, overexpression of an EF-hand deficient mutant of the mtCU gatekeeper MICU1 reduced the cooperativity of mitochondrial Ca2+ uptake. Interestingly, the IP3-induced [Ca2+]m signal plateaued at high Ca2 + ER, indicating activation of a matrix Ca2+ binding/chelating species. Mitochondria thus seem to maintain a "working [Ca2+]m range" via a low-affinity and high-capacity buffer species, and the ER loading steeply enhances the IP3R-linked [Ca2+]m signals in this working range.

Keywords:  ER; calcium; calcium buffering; cooperativity; mitochondria; uniporter

DOI:  https://doi.org/10.1177/25152564241229273
Mitochondrial Commun. 2024 ;2 14-20

Mitochondrial Calcium Transport During Autophagy Initiation.

Sujyoti Chandra, Parul Katiyar, Aarooran S Durairaj, Xinnan Wang.

  While it has been shown that Ca2+ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca2+ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca2+ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca2+ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca2+ transport and Ca2+ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca2+ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca2+ influx is faster, which may slow the ensuing mitophagy.

Keywords:  ER Ca2+ transient; IP3R; MCU; Parkinson; RyR; autophagy; mitochondrial Ca2+ uptake; mitophagy

DOI:  https://doi.org/10.1016/j.mitoco.2024.01.002
J Biol Chem. 2024 Feb 13. pii: S0021-9258(24)00130-3. [Epub ahead of print] 105754

A KDELR-mediated ER-retrieval system modulates mitochondrial functions via the unfolded protein response in fission yeast.

Mengdan Zhu, Zheng Fang, Yifan Wu, Fenfen Dong, Yuzhou Wang, Fan Zheng, Xiaopeng Ma, Shisong Ma, Jiajia He, Xing Liu, Xuebiao Yao, Chuanhai Fu.

  KDELR (Erd2 in yeasts) is a receptor protein that retrieves ER-resident proteins from the Golgi apparatus. However, the role of the KDELR-mediated ER-retrieval system in regulating cellular homeostasis remains elusive. Here we show that the absence of Erd2 triggers the unfolded protein response (UPR) and enhances mitochondrial respiration and reactive oxygen species (ROS) in an UPR-dependent manner in the fission yeast Schizosaccharomyces Pombe. Moreover, we perform transcriptomic analysis and find that the expression of genes related to mitochondrial respiration and the tricarboxylic acid cycle is upregulated in a UPR-dependent manner in cells lacking Erd2. The increased mitochondrial respiration and ROS production is required for cell survival in the absence of Erd2. Therefore, our findings reveal a novel role of the KDELR/Erd2-mediated ER-retrieval system in modulating mitochondrial functions and highlight its importance for cellular homeostasis in the fission yeast.

Keywords:  ER; Golgi; KDELR; Mitochondria; Schizosaccharomyces pombe; UPR/

DOI:  https://doi.org/10.1016/j.jbc.2024.105754
Autophagy. 2024 Feb 15. 1-9

Did mitophagy follow the origin of mitochondria?

Mauro Degli Esposti.

  Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy signaling.Abbreviations: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; ATG, autophagy related; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CALCOCO, calcium binding and coiled-coil domain; CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FBXL4, F-box and leucine rich repeat protein 4; FUNDC1, FUN14 domain containing 1; GABARAPL1, GABA type A receptor associated protein like 1; HIF, hypoxia inducible factor; IMM, inner mitochondrial membrane; LBPA/BMP, lysobisphosphatidic acid; LIR, LC3-interacting region; LPA, lysophosphatidic acid; MAM, mitochondria-associated membranes; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MCL, monolysocardiolipin; ML, maximum likelihood; NBR1, NBR1 autophagy cargo receptor; OMM, outer mitochondrial membrane; PA, phosphatidic acid; PACS2, phosphofurin acidic cluster sorting protein 2; PC/PLC, phosphatidylcholine; PE, phosphatidylethanolamine; PHB2, prohibitin 2; PINK1, PTEN induced kinase 1; PtdIns, phosphatidylinositol; SAR, Stramenopiles, Apicomplexa and Rhizaria; TAX1BP1, Tax1 binding protein 1; ULK1, unc-51 like autophagy activating kinase 1; VDAC/porin, voltage dependent anion channel.

Keywords:  BNIP3; cardiolipin; evolution; membrane dynamics; mitochondria; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2307215