bims-mitdyn 2022-07-31 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2022‒07‒31
sixteen papers selected by
Edmond Chan
Queen’s University, School of Medicine

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function.
Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts.
Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases.
Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle.
Catalytic cycling of human mitochondrial Lon protease.
Succinate dehydrogenase inversely regulates red cell distribution width and healthy lifespan in chronically hypoxic mice.
Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.
Epigenetic control of mitochondrial fission enables hepatic stellate cells activation in liver fibrosis via PGC-1α-Drp1 pathway.
Mitochondrial control of inflammation.
EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.
The hexokinase "HKDC1" interaction with the mitochondria is essential for liver cancer progression.
A secretory form of Parkin-independent mitophagy contributes to the repertoire of extracellular vesicles released into the tumour interstitial fluid in vivo.
A network of cytosolic (co)chaperones promotes the biogenesis of mitochondrial signal-anchored outer membrane proteins.
TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.
Autophagic secretion of mitochondria (ASM): An alternative way for getting rid of damaged mitochondria.
Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Proc Natl Acad Sci U S A. 2022 Aug 02. 119(31): e2205469119

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function.

Minghui Xia, Cai Zhang, Yufei Chen, Xiujuan Zhao, Si Zhang, Yang Liu, You Cai, Zhengping Wei, Qiuyang Du, Wenting Yu, Chun Zhou, Hongjun Xiao, Guihua Wang, Xiang Cheng, Heng Mei, Arian Laurence, Jing Wang, Yu Hu, Huabin Li, Xiang-Ping Yang.

  T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4+ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.

Keywords:  Myc; TFEB; Treg; mTORC1; mitochondrial

DOI:  https://doi.org/10.1073/pnas.2205469119
Nat Commun. 2022 Jul 25. 13(1): 4303

Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts.

Kangqiang Qiu, Weiwei Zou, Hongbao Fang, Mingang Hao, Kritika Mehta, Zhiqi Tian, Jun-Lin Guan, Kai Zhang, Taosheng Huang, Jiajie Diao.

Mitochondria are highly dynamic organelles whose fragmentation by fission is critical to their functional integrity and cellular homeostasis. Here, we develop a method via optogenetic control of mitochondria-lysosome contacts (MLCs) to induce mitochondrial fission with spatiotemporal accuracy. MLCs can be achieved by blue-light-induced association of mitochondria and lysosomes through various photoactivatable dimerizers. Real-time optogenetic induction of mitochondrial fission is tracked in living cells to measure the fission rate. The optogenetic method partially restores the mitochondrial functions of SLC25A46-/- cells, which display defects in mitochondrial fission and hyperfused mitochondria. The optogenetic MLCs system thus provides a platform for studying mitochondrial fission and treating mitochondrial diseases.

DOI: https://doi.org/10.1038/s41467-022-31970-5
Nat Commun. 2022 Jul 29. 13(1): 4413

Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases.

Satoshi Watanabe, Yuta Nihongaki, Kie Itoh, Toru Uyama, Satoshi Toda, Shigeki Watanabe, Takanari Inoue.

Organelles vitally achieve multifaceted functions to maintain cellular homeostasis. Genetic and pharmacological approaches to manipulate individual organelles are powerful in probing their physiological roles. However, many of them are either slow in action, limited to certain organelles, or rely on toxic agents. Here, we design a generalizable molecular tool utilizing phospholipase A/acyltransferases (PLAATs) for rapid defunctionalization of organelles via remodeling of the membrane phospholipids. In particular, we identify catalytically active PLAAT truncates with minimal unfavorable characteristics. Chemically-induced translocation of the optimized PLAAT to the mitochondria surface results in their rapid deformation in a phospholipase activity dependent manner, followed by loss of luminal proteins as well as dissipated membrane potential, thus invalidating the functionality. To demonstrate wide applicability, we then adapt the molecular tool in peroxisomes, and observe leakage of matrix-resident functional proteins. The technique is compatible with optogenetic control, viral delivery and operation in primary neuronal cultures. Due to such versatility, the PLAAT strategy should prove useful in studying organelle biology of diverse contexts.

DOI: https://doi.org/10.1038/s41467-022-31946-5
Cell Rep. 2022 Jul 26. pii: S2211-1247(22)00907-X. [Epub ahead of print]40(4): 111105

Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle.

Guillaume Tournaire, Shauni Loopmans, Steve Stegen, Gianmarco Rinaldi, Guy Eelen, Sophie Torrekens, Karen Moermans, Peter Carmeliet, Bart Ghesquière, Bernard Thienpont, Sarah-Maria Fendt, Nick van Gastel, Geert Carmeliet.

  A functional electron transport chain (ETC) is crucial for supporting bioenergetics and biosynthesis. Accordingly, ETC inhibition decreases proliferation in cancer cells but does not seem to impair stem cell proliferation. However, it remains unclear how stem cells metabolically adapt. In this study, we show that pharmacological inhibition of complex III of the ETC in skeletal stem and progenitor cells induces glycolysis side pathways and reroutes the tricarboxylic acid (TCA) cycle to regenerate NAD+ and preserve cell proliferation. These metabolic changes also culminate in increased succinate and 2-hydroxyglutarate levels that inhibit Ten-eleven translocation (TET) DNA demethylase activity, thereby preserving self-renewal and multilineage potential. Mechanistically, mitochondrial malate dehydrogenase and reverse succinate dehydrogenase activity proved to be essential for the metabolic rewiring in response to ETC inhibition. Together, these data show that the metabolic plasticity of skeletal stem and progenitor cells allows them to bypass ETC blockade and preserve their self-renewal.

Keywords:  CP: Metabolism; CP: Stem cell research; NAD regeneration; TCA rerouting; TET activity; cell-based regenerative medicine; electron transport chain; metabolic plasticity; proliferation; reverse succinate dehydrogenase; self-renewal; skeletal stem cells

DOI:  https://doi.org/10.1016/j.celrep.2022.111105
Structure. 2022 Jul 12. pii: S0969-2126(22)00269-6. [Epub ahead of print]

Catalytic cycling of human mitochondrial Lon protease.

Inayathulla Mohammed, Kai A Schmitz, Niko Schenck, Dimitrios Balasopoulos, Annika Topitsch, Timm Maier, Jan Pieter Abrahams.

  The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational states by cryoelectron microscopy (cryo-EM). The flexible assembly of N-terminal domains had 3-fold symmetry, and its orientation depended on the conformational state. We show that a conserved structural motif around T803 with a high similarity to the trypsin catalytic triad is essential for proteolysis. We show that LonP1 is not regulated by redox potential, despite the presence of two conserved cysteines at disulfide-bonding distance in its unfoldase core. Our data indicate how sequential ATP hydrolysis controls substrate protein translocation in a 6-fold binding change mechanism. Substrate protein translocation, rather than ATP hydrolysis, is a rate-limiting step, suggesting that LonP1 is a Brownian ratchet with ATP hydrolysis preventing translocation reversal. 3-fold rocking motions of the flexible N-domain assembly may assist thermal unfolding of the substrate protein.

Keywords:  AAA+ protein; chaperone; molecular motor; proteolysis

DOI:  https://doi.org/10.1016/j.str.2022.06.006
JCI Insight. 2022 Jul 26. pii: e158737. [Epub ahead of print]

Succinate dehydrogenase inversely regulates red cell distribution width and healthy lifespan in chronically hypoxic mice.

Bora E Baysal, Abdulrahman A Alahmari, Tori C Rodrick, Debra Tabaczynski, Leslie Curtin, Mukund Seshadri, Drew R Jones, Sandra Sexton.

  Increased red cell distribution width (RDW), which measures erythrocyte volume (MCV) variability (anisocytosis), has been linked to early mortality in many diseases and in older adults through unknown mechanisms. Hypoxic stress has been proposed as a potential mechanism. However, experimental models to investigate the link between increased RDW and reduced survival are lacking. Here, we show that lifelong hypobaric hypoxia (~10% O2) increases erythrocyte numbers, hemoglobin and RDW, while reducing longevity in male mice. Compound heterozygous knockout (chKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc and Sdhd reduce Sdh subunit protein levels, RDW, and increase healthy lifespan compared to wild-type (WT) mice in chronic hypoxia. RDW-SD, a direct measure of MCV variability, and the standard deviation of MCV (1SD-RDW) show the most statistically significant reductions in Sdh hKO mice. Tissue metabolomic profiling of 147 common metabolites shows the largest increase in succinate with elevated succinate to fumarate and succinate to oxoglutarate (2-ketoglutarate) ratios in Sdh hKO mice. These results demonstrate that mitochondrial complex II level is an underlying determinant of both RDW and healthy lifespan in hypoxia, and suggest that therapeutic targeting of Sdh might reduce high RDW-associated clinical mortality in hypoxic diseases.

Keywords:  Hematology; Hypoxia; Mitochondria; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.158737
JCI Insight. 2022 Jul 26. pii: e156346. [Epub ahead of print]

Dichloroacetate improves mitochondrial function, physiology, and morphology in FBXL4 disease models.

Manuela Lavorato, Eiko Nakamaru-Ogiso, Neal D Mathew, Elizabeth Herman, Nina K Shah, Suraiya Haroon, Rui Xiao, Christoph Seiler, Marni J Falk.

  Pathogenic variants in the human F Box and Leucine Rich Repeat Protein 4 (FBXL4) gene result in an autosomal recessive, multi-systemic, mitochondrial disorder involving variable mitochondrial depletion and respiratory chain (RC) complex deficiencies with lactic acidemia. As no FDA-approved effective therapies exist, we sought to characterize translational C. elegans and zebrafish animal models, as well as human fibroblasts, to study FBXL4-/- disease mechanisms and identify preclinical therapeutic leads. Developmental delay, impaired fecundity and neurologic and/or muscular activity, mitochondrial dysfunction, and altered lactate metabolism were identified in fbxl-1(ok3741) C. elegans. Detailed studies of a pyruvate dehydrogenase complex activator, dichloroacetate (DCA) in fbxl-1(ok3741) C. elegans demonstrated its beneficial effects on fecundity, neuromotor activity, and mitochondrial function. Validation studies were performed in fbxl4sa12470 zebrafish larvae and in FBXL4-/- human fibroblasts, which showed DCA efficacy in preventing brain damage, impairment of neurologic and/or muscular function, mitochondrial biochemical dysfunction, and stress-induced morphologic and ultrastructural mitochondrial defects. These data demonstrate that fbxl-1 (ok3741) C. elegans and fbxl4sa12470 zebrafish provide robust translational models to study mechanisms and identify preclinical therapeutic candidates for FBXL4-/- disease. Further, DCA is a lead therapeutic candidate with therapeutic benefit on diverse aspects of survival, neurologic and/or muscular function, and mitochondrial physiology that warrants rigorous clinical trial study in human subjects with FBXL4-/- disease.

Keywords:  Drug therapy; Genetic diseases; Genetics; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.156346
Mitochondrion. 2022 Jul 26. pii: S1567-7249(22)00069-1. [Epub ahead of print]

Epigenetic control of mitochondrial fission enables hepatic stellate cells activation in liver fibrosis via PGC-1α-Drp1 pathway.

Jing-Jing Yang, Juan Wang, Yang Yang, Feng Sun, Yan Yang, Jun Li, Hui Tao, Chao Lu.

  Although excessive mitochondrial fission is linked to cell activation, its significance in hepatic stellate cells (HSCs) activation and liver fibrosis is unknown. Here we show that excessive mitochondrial fission triggers HSCs activation and liver fibrosis degradation by the epigenetic regulation. We used a combination of in vitro and in vivo models, including HSCs and clinical cases or CCl4-induced liver fibrosis mice, was performed to investigate the regulation and function of mitochondrial fission in HSCs activation and liver fibrosis. Herein, we show that DNMT3A and Drp1 is up regulated in fibrosis livers and mice liver fibrosis tissues, while PGC-1α was decreased. Interestingly, down expression of DNMT3A substantially reduced Drp1 levels, collagen accumulation, and interstitial fibrosis, while significantly increased PGC-1α levels. Furthermore, silencing DNMT3A remarkably inhibits HSCs activation and mitochondrial fission both in vivo and in vitro. Mechanistically, co-immunoprecipitation analysis revealed that DNMT3A bound to pull down the protein of PGC-1α. These findings indicated that epigenetic control of mitochondrial fission enables HSCs activation in liver fibrosis via PGC-1α-Drp1 pathway, and provide new insight into the relationship between mitochondrial fission and liver fibrosis.

Keywords:  Activation; DNMT3A; Drp1; Hepatic stellate cells; Liver fibrosis; Mitochondrial fission

DOI:  https://doi.org/10.1016/j.mito.2022.07.005
Nat Rev Immunol. 2022 Jul 25.

Mitochondrial control of inflammation.

Saverio Marchi, Emma Guilbaud, Stephen W G Tait, Takahiro Yamazaki, Lorenzo Galluzzi.

Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.

DOI: https://doi.org/10.1038/s41577-022-00760-x
Curr Biol. 2022 Jul 19. pii: S0960-9822(22)01104-6. [Epub ahead of print]

EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation.

Chenge Zhang, Yinhua Jin, Marco Marchetti, Mitchell R Lewis, Omar T Hammouda, Bruce A Edgar.

  EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Keywords:  Ets21C; ISC; Pointed; intestinal stem cell; mitochondrial biogenesis; mtTFB2; proliferation

DOI:  https://doi.org/10.1016/j.cub.2022.07.003
Cell Death Dis. 2022 Jul 28. 13(7): 660

The hexokinase "HKDC1" interaction with the mitochondria is essential for liver cancer progression.

Md Wasim Khan, Alexander R Terry, Medha Priyadarshini, Vladimir Ilievski, Zeenat Farooq, Grace Guzman, Jose Cordoba-Chacon, Issam Ben-Sahra, Barton Wicksteed, Brian T Layden.

Liver cancer (LC) is the fourth leading cause of death from cancer malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in LC compared to healthy liver tissue. Using a combination of in vitro and in vivo tools, we examined the role of HKDC1 in LC development and progression. Importantly, HKDC1 ablation stops LC development and progression via its action at the mitochondria by promoting metabolic reprogramming and a shift of glucose flux away from the TCA cycle. HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy, which cannot be compensated by enhanced glucose uptake. Moreover, we show that the interaction of HKDC1 with the mitochondria is essential for its role in LC progression, and without this interaction, mitochondrial dysfunction occurs. As HKDC1 is highly expressed in LC cells, but only to a minimal degree in hepatocytes under normal conditions, targeting HKDC1, specifically its interaction with the mitochondria, may represent a highly selective approach to target cancer cells in LC.

DOI: https://doi.org/10.1038/s41419-022-04999-z
J Extracell Vesicles. 2022 Jul;11(7): e12244

A secretory form of Parkin-independent mitophagy contributes to the repertoire of extracellular vesicles released into the tumour interstitial fluid in vivo.

Marissa Howard, James Erickson, Zachary Cuba, Shawn Kim, Weidong Zhou, Purva Gade, Rachel Carter, Kelsey Mitchell, Heather Branscome, Daivik Siddhi, Fatimah Alanazi, Yuriy Kim, Robyn P Araujo, Amanda Haymond, Alessandra Luchini, Fatah Kashanchi, Lance A Liotta.

  We characterized the in vivo interstitial fluid (IF) content of extracellular vesicles (EVs) using the GFP-4T1 syngeneic murine cancer model to study EVs in-transit to the draining lymph node. GFP labelling confirmed the IF EV tumour cell origin. Molecular analysis revealed an abundance of IF EV-associated proteins specifically involved in mitophagy and secretory autophagy. A set of proteins required for sequential steps of fission-induced mitophagy preferentially populated the CD81+/PD-L1+ IF EVs; PINK1, TOM20, and ARIH1 E3 ubiquitin ligase (required for Parkin-independent mitophagy), DRP1 and FIS1 (mitochondrial peripheral fission), VDAC-1 (ubiquitination state triggers mitophagy away from apoptosis), VPS35, SEC22b, and Rab33b (vacuolar sorting). Comparing in vivo IF EVs to in vitro EVs revealed 40% concordance, with an elevation of mitophagy proteins in the CD81+ EVs for both murine and human cell lines subjected to metabolic stress. The export of cellular mitochondria proteins to CD81+ EVs was confirmed by density gradient isolation from the bulk EV isolate followed by anti-CD81 immunoprecipitation, molecular sieve chromatography, and MitoTracker export into CD81+ EVs. We propose the 4T1 in vivo model as a versatile tool to functionally characterize IF EVs. IF EV export of fission mitophagy proteins has broad implications for mitochondrial function and cellular immunology.

Keywords:  autophagosome; autophagy; breast cancer; extracellular vesicle; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/jev2.12244
Elife. 2022 Jul 25. pii: e77706. [Epub ahead of print]11

A network of cytosolic (co)chaperones promotes the biogenesis of mitochondrial signal-anchored outer membrane proteins.

Layla Drwesh, Benjamin Heim, Max Graf, Linda Kehr, Lea Hansen-Palmus, Mirita Franz-Wachtel, Boris Macek, Hubert Kalbacher, Johannes Buchner, Doron Rapaport.

  Signal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on cytosolic ribosomes, and are then targeted to the organelle and inserted into its OM by import factors. Recently, research on the insertion mechanisms of these proteins into the mitochondrial OM have gained a lot of attention. In contrast, the early cytosolic steps of their biogenesis are unresolved. Using various proteins from this category and a broad set of in vivo, in organello, and in vitro assays, we reconstituted the early steps of their biogenesis. We identified a subset of molecular (co)chaperones that interact with newly synthesized SA proteins, namely, Hsp70 and Hsp90 chaperones and co-chaperones from the Hsp40 family like Ydj1 and Sis1. These interactions were mediated by the hydrophobic transmembrane segments of the SA proteins. We further demonstrate that interfering with these interactions inhibits the biogenesis of SA proteins to a various extent. Finally, we could demonstrate direct interaction of peptides corresponding to the transmembrane segments of SA proteins with the (co)chaperones and reconstitute in vitro the transfer of such peptides from the Hsp70 chaperone to the mitochondrial Tom70 receptor. Collectively, this study unravels an array of cytosolic chaperones and mitochondrial import factors that facilitates the targeting and membrane integration of mitochondrial SA proteins.

Keywords:  S. cerevisiae; biochemistry; chemical biology

DOI:  https://doi.org/10.7554/eLife.77706
Autophagy. 2022 Jul 27. 1-26

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability.

Surbhi Chouhan, Mithila Sawant, Cody Weimholt, Jingqin Luo, Robert W Sprung, Mailyn Terrado, David M Mueller, H Shelton Earp, Nupam P Mahajan.

  The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as "mitocans" to induce cancer-specific mitophagy.AbbreviationsATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type.

Keywords:  ATP5F1A; ATP5IF1; TNK2/ACK1; mitochondrial dysfunction; mitochondrial vulnerability; mitophagy; tyrosine phosphorylation

DOI:  https://doi.org/10.1080/15548627.2022.2103961
Autophagy. 2022 Jul 28.

Autophagic secretion of mitochondria (ASM): An alternative way for getting rid of damaged mitochondria.

Hayden Weng Siong Tan, Guang Lu, Han-Ming Shen.

  PINK1-PRKN/Parkin-mediated mitophagy represents an important mitochondrial quality control (MQC) pathway that clears damaged/dysfunctional mitochondria. Although the conjugation of mammalian Atg8-family proteins (mATG8s) to phosphatidylethanolamine (PE) is a defining step in autophagy, its role in mitophagy remains unclear. In our recent study, we found that the mATG8 conjugation system is not required for PINK1-PRKN-mediated mitochondria clearance. Instead, mATG8 conjugation system-independent mitochondria clearance relies on secretory autophagy, in a process we term as the autophagic secretion of mitochondria (ASM). As ASM results in the spurious activation of the CGAS-STING1 pathway, we propose that defects in mATG8 lipidation may promote inflammation through ASM.

Keywords:  Extracellular vesicles; PINK1-PRKN; inflammation; mATG8 conjugation system; mitochondrial quality control; mitophagy; secretory autophagy

DOI:  https://doi.org/10.1080/15548627.2022.2107310
Sci Adv. 2022 Jul 29. 8(30): eabo0340

Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4.

Qiqi Guo, Zhisheng Xu, Danxia Zhou, Tingting Fu, Wen Wang, Wanping Sun, Liwei Xiao, Lin Liu, Chenyun Ding, Yujing Yin, Zheng Zhou, Zongchao Sun, Yuangang Zhu, Wenjing Zhou, Yuhuan Jia, Jiachen Xue, Yuncong Chen, Xiao-Wei Chen, Hai-Long Piao, Bin Lu, Zhenji Gan.

Mitochondrial quality in skeletal muscle is crucial for maintaining energy homeostasis during metabolic stresses. However, how muscle mitochondrial quality is controlled and its physiological impacts remain unclear. Here, we demonstrate that mitoprotease LONP1 is essential for preserving muscle mitochondrial proteostasis and systemic metabolic homeostasis. Skeletal muscle-specific deletion of Lon protease homolog, mitochondrial (LONP1) impaired mitochondrial protein turnover, leading to muscle mitochondrial proteostasis stress. A benefit of this adaptive response was the complete resistance to diet-induced obesity. These favorable metabolic phenotypes were recapitulated in mice overexpressing LONP1 substrate ΔOTC in muscle mitochondria. Mechanistically, mitochondrial proteostasis imbalance elicits an unfolded protein response (UPRmt) in muscle that acts distally to modulate adipose tissue and liver metabolism. Unexpectedly, contrary to its previously proposed role, ATF4 is dispensable for the long-range protective response of skeletal muscle. Thus, these findings reveal a pivotal role of LONP1-dependent mitochondrial proteostasis in directing muscle UPRmt to regulate systemic metabolism.

DOI: https://doi.org/10.1126/sciadv.abo0340