bims-mitdyn 2021-03-21 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2021–03–21
seventeen papers selected by
Edmond Chan, Queen’s University, School of Medicine

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.
Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis.
Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors.
A nuclear-based quality control pathway for non-imported mitochondrial proteins.
Toxoplasma gondii association with host mitochondria requires key mitochondrial protein import machinery.
An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans.
Dynamic interplay between the co-opted Fis1 mitochondrial fission protein and membrane contact site proteins in supporting tombusvirus replication.
Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production.
Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process.
AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy.
Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.
Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers.
The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress.
Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response.
Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.
The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways.
Mitochondrial dynamics in health and disease.

Cell Rep. 2021 Mar 16. pii: S2211-1247(21)00183-2. [Epub ahead of print]34(11): 108869

The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.

Michelle Grace Acoba, Ebru S Selen Alpergin, Santosh Renuse, Lucía Fernández-Del-Río, Ya-Wen Lu, Oleh Khalimonchuk, Catherine F Clarke, Akhilesh Pandey, Michael J Wolfgang, Steven M Claypool.

  Mitochondrial carriers (MCs) mediate the passage of small molecules across the inner mitochondrial membrane (IMM), enabling regulated crosstalk between compartmentalized reactions. Despite MCs representing the largest family of solute carriers in mammals, most have not been subjected to a comprehensive investigation, limiting our understanding of their metabolic contributions. Here, we functionally characterize SFXN1, a member of the non-canonical, sideroflexin family. We find that SFXN1, an integral IMM protein with an uneven number of transmembrane domains, is a TIM22 complex substrate. SFXN1 deficiency leads to mitochondrial respiratory chain impairments, most detrimental to complex III (CIII) biogenesis, activity, and assembly, compromising coenzyme Q levels. The CIII dysfunction is independent of one-carbon metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, SFXN1 supports CIII function by participating in heme and α-ketoglutarate metabolism. Our findings highlight the multiple ways that SFXN1-based amino acid transport impacts mitochondrial and cellular metabolic efficiency.

Keywords:  Complex III; OXPHOS; SFXN1; TIM22 complex; amino acid; heme; mitochondria; mitochondrial carrier; serine; sideroflexin

DOI:  https://doi.org/10.1016/j.celrep.2021.108869
Cell Rep. 2021 Mar 16. pii: S2211-1247(21)00187-X. [Epub ahead of print]34(11): 108873

Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis.

Irene Anastasia, Nicolò Ilacqua, Andrea Raimondi, Philippe Lemieux, Rana Ghandehari-Alavijeh, Guilhem Faure, Sergei L Mekhedov, Kevin J Williams, Federico Caicci, Giorgio Valle, Marta Giacomello, Ariel D Quiroga, Richard Lehner, Michael J Miksis, Katalin Toth, Thomas Q de Aguiar Vallim, Eugene V Koonin, Luca Scorrano, Luca Pellegrini.

  Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.

Keywords:  MAM; MUP; Rrbp1; VLDL; endoplasmic reticulum; inter-organelle contact; lipoprotein; liver metabolism; mitochondria; wrappER

DOI:  https://doi.org/10.1016/j.celrep.2021.108873
iScience. 2021 Mar 19. 24(3): 102196

Impaired phosphatidylethanolamine metabolism activates a reversible stress response that detects and resolves mutant mitochondrial precursors.

Pingdewinde N Sam, Elizabeth Calzada, Michelle Grace Acoba, Tian Zhao, Yasunori Watanabe, Anahita Nejatfard, Jonathan C Trinidad, Timothy E Shutt, Sonya E Neal, Steven M Claypool.

  Phosphatidylethanolamine (PE) made in mitochondria has long been recognized as an important precursor for phosphatidylcholine production that occurs in the endoplasmic reticulum (ER). Recently, the strict mitochondrial localization of the enzyme that makes PE in the mitochondrion, phosphatidylserine decarboxylase 1 (Psd1), was questioned. Since a dual localization of Psd1 to the ER would have far-reaching implications, we initiated our study to independently re-assess the subcellular distribution of Psd1. Our results support the unavoidable conclusion that the vast majority, if not all, of functional Psd1 resides in the mitochondrion. Through our efforts, we discovered that mutant forms of Psd1 that impair a self-processing step needed for it to become functional are dually localized to the ER when expressed in a PE-limiting environment. We conclude that severely impaired cellular PE metabolism provokes an ER-assisted adaptive response that is capable of identifying and resolving nonfunctional mitochondrial precursors.

Keywords:  Cell Biology; Molecular Physiology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2021.102196
Elife. 2021 Mar 18. pii: e61230. [Epub ahead of print]10

A nuclear-based quality control pathway for non-imported mitochondrial proteins.

Viplendra Ps Shakya, William A Barbeau, Tianyao Xiao, Christina S Knutson, Max H Schuler, Adam L Hughes.

  Mitochondrial import deficiency causes cellular toxicity due to the accumulation of non-imported mitochondrial precursor proteins, termed mitoprotein-induced stress. Despite the burden mis-localized mitochondrial precursors place on cells, our understanding of the systems that dispose of these proteins is incomplete. Here, we cataloged the location and steady-state abundance of mitochondrial precursor proteins during mitochondrial impairment in S. cerevisiae. We found that a number of non-imported mitochondrial proteins localize to the nucleus, where they are subjected to proteasome-dependent degradation through a process we term nuclear-associated mitoprotein degradation (mitoNUC). Recognition and destruction of mitochondrial precursors by the mitoNUC pathway requires the presence of an N-terminal mitochondrial targeting sequence (MTS) and is mediated by combined action of the E3 ubiquitin ligases San1, Ubr1, and Doa10. Impaired breakdown of precursors leads to alternative sequestration in nuclear-associated foci. These results identify the nucleus as an important destination for the disposal of non-imported mitochondrial precursors.

Keywords:  S. cerevisiae; cell biology

DOI:  https://doi.org/10.7554/eLife.61230
Proc Natl Acad Sci U S A. 2021 Mar 23. pii: e2013336118. [Epub ahead of print]118(12):

Toxoplasma gondii association with host mitochondria requires key mitochondrial protein import machinery.

Matthew L Blank, Jing Xia, Mary M Morcos, Mai Sun, Pamela S Cantrell, Yang Liu, Xuemei Zeng, Cameron J Powell, Nathan Yates, Martin J Boulanger, Jon P Boyle.

  Host mitochondrial association (HMA) is a well-known phenomenon during Toxoplasma gondii infection of the host cell. The T. gondii locus mitochondrial association factor 1 (MAF1) is required for HMA and MAF1 encodes distinct paralogs of secreted dense granule effector proteins, some of which mediate the HMA phenotype (MAF1b paralogs drive HMA; MAF1a paralogs do not). To identify host proteins required for MAF1b-mediated HMA, we performed unbiased, label-free quantitative proteomics on host cells infected with type II parasites expressing MAF1b, MAF1a, and an HMA-incompetent MAF1b mutant. Across these samples, we identified ∼1,360 MAF1-interacting proteins, but only 13 that were significantly and uniquely enriched in MAF1b pull-downs. The gene products include multiple mitochondria-associated proteins, including those that traffic to the mitochondrial outer membrane. Based on follow-up endoribonuclease-prepared short interfering RNA (esiRNA) experiments targeting these candidate MAF1b-targeted host factors, we determined that the mitochondrial receptor protein TOM70 and mitochondria-specific chaperone HSPA9 were essential mediators of HMA. Additionally, the enrichment of TOM70 at the parasitophorous vacuole membrane interface suggests parasite-driven sequestration of TOM70 by the parasite. These results show that the interface between the T. gondii vacuole and the host mitochondria is characterized by interactions between a single parasite effector and multiple target host proteins, some of which are critical for the HMA phenotype itself. The elucidation of the functional members of this complex will permit us to explain the link between HMA and changes in the biology of the host cell.

Keywords:  Toxoplasma gondii; mitochondria; neofunctionalization; tandem gene expansion; virulence

DOI:  https://doi.org/10.1073/pnas.2013336118
PLoS Biol. 2021 Mar 15. 19(3): e3000957

An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence in Candida albicans.

Zeinab Mamouei, Shakti Singh, Bernard Lemire, Yiyou Gu, Abdullah Alqarihi, Sunna Nabeela, Dongmei Li, Ashraf Ibrahim, Priya Uppuluri.

A forward genetic screening approach identified orf19.2500 as a gene controlling Candida albicans biofilm dispersal and biofilm detachment. Three-dimensional (3D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. The C. albicans orf19.2500 is distinguished by 3 evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of the NADH ubiquinone oxidoreductase Complex I (CI) of the respiratory electron transport chain (ETC) and was thereby named NDU1. NDU1 is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets the Candida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary "gain" of new amino acid inserts that are also the functional hub of the protein.

DOI: https://doi.org/10.1371/journal.pbio.3000957
PLoS Pathog. 2021 Mar 16. 17(3): e1009423

Dynamic interplay between the co-opted Fis1 mitochondrial fission protein and membrane contact site proteins in supporting tombusvirus replication.

Wenwu Lin, Zhike Feng, K Reddisiva Prasanth, Yuyan Liu, Peter D Nagy.

Plus-stranded RNA viruses have limited coding capacity and have to co-opt numerous pro-viral host factors to support their replication. Many of the co-opted host factors support the biogenesis of the viral replication compartments and the formation of viral replicase complexes on subverted subcellular membrane surfaces. Tomato bushy stunt virus (TBSV) exploits peroxisomal membranes, whereas the closely-related carnation Italian ringspot virus (CIRV) hijacks the outer membranes of mitochondria. How these organellar membranes can be recruited into pro-viral roles is not completely understood. Here, we show that the highly conserved Fis1 mitochondrial fission protein is co-opted by both TBSV and CIRV via direct interactions with the p33/p36 replication proteins. Deletion of FIS1 in yeast or knockdown of the homologous Fis1 in plants inhibits tombusvirus replication. Instead of the canonical function in mitochondrial fission and peroxisome division, the tethering function of Fis1 is exploited by tombusviruses to facilitate the subversion of membrane contact site (MCS) proteins and peroxisomal/mitochondrial membranes for the biogenesis of the replication compartment. We propose that the dynamic interactions of Fis1 with MCS proteins, such as the ER resident VAP tethering proteins, Sac1 PI4P phosphatase and the cytosolic OSBP-like oxysterol-binding proteins, promote the formation and facilitate the stabilization of virus-induced vMCSs, which enrich sterols within the replication compartment. We show that this novel function of Fis1 is exploited by tombusviruses to build nuclease-insensitive viral replication compartment.

DOI: https://doi.org/10.1371/journal.ppat.1009423
Cell Death Differ. 2021 Mar 15.

Mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming via p53 activation and reducing acetyl-CoA production.

Kunlun Yin, Jordan Lee, Zhaoli Liu, Hyeoncheol Kim, David R Martin, Dandan Wu, Meilian Liu, Xiang Xue.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.

DOI: https://doi.org/10.1038/s41418-021-00760-9
J Cell Biol. 2021 Apr 05. pii: e201909139. [Epub ahead of print]220(4):

Autophagy facilitates mitochondrial rebuilding after acute heat stress via a DRP-1-dependent process.

Yanfang Chen, Romane Leboutet, Céline Largeau, Siham Zentout, Christophe Lefebvre, Agnès Delahodde, Emmanuel Culetto, Renaud Legouis.

Acute heat stress (aHS) can induce strong developmental defects in Caenorhabditis elegans larva but not lethality or sterility. This stress results in transitory fragmentation of mitochondria, formation of aggregates in the matrix, and decrease of mitochondrial respiration. Moreover, active autophagic flux associated with mitophagy events enables the rebuilding of the mitochondrial network and developmental recovery, showing that the autophagic response is protective. This adaptation to aHS does not require Pink1/Parkin or the mitophagy receptors DCT-1/NIX and FUNDC1. We also find that mitochondria are a major site for autophagosome biogenesis in the epidermis in both standard and heat stress conditions. In addition, we report that the depletion of the dynamin-related protein 1 (DRP-1) affects autophagic processes and the adaptation to aHS. In drp-1 animals, the abnormal mitochondria tend to modify their shape upon aHS but are unable to achieve fragmentation. Autophagy is induced, but autophagosomes are abnormally elongated and clustered on mitochondria. Our data support a role for DRP-1 in coordinating mitochondrial fission and autophagosome biogenesis in stress conditions.

DOI: https://doi.org/10.1083/jcb.201909139
Autophagy. 2021 Mar 14. 1-22

AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy.

Xinyi Lu, Wenting Xuan, Juanjuan Li, Hongwei Yao, Cheng Huang, Jun Li.

  Recent reports indicated that mitophagy protects against alcohol-induced liver injury, which helps remove damaged mitochondria to reduce the accumulation of reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction research. However, the inner mechanism, whether AMPK can regulate mitophagy in ALD, remains unknown. Here we found that AMPK can significantly reduce alcohol-induced liver injury and enhances hepatocytes' mitophagy level. Next, we identified that AMPK rescued alcohol-induced low expression of UQCRC2 (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression (OE) can significantly increase mitophagy to attenuate liver injury. Also, we identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays helped us understand that AMPK enhanced UQCRC2 gene transcription through activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the regulation of mitophagy levels in the liver, suggesting a possible therapeutic strategy to treat ALD.Abbreviations: AAV: AENO-associated virus; ALD: alcoholic liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic obstructive pulmonary disease; EM: electron microscope; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WB: western blot; ΔΨ: mitochondrial membrane potential.

Keywords:  AMPK; bioinformatics; mitophagy; rna-seq; transcription factor; uqcrc2

DOI:  https://doi.org/10.1080/15548627.2021.1886829
Dev Cell. 2021 Mar 09. pii: S1534-5807(21)00162-3. [Epub ahead of print]

Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.

Wanchun Yang, Dejiang Pang, Mina Chen, Chongyangzi Du, Lanlan Jia, Luoling Wang, Yunling He, Wanxiang Jiang, Liping Luo, Zongyan Yu, Mengqian Mao, Qiuyun Yuan, Ping Tang, Xiaoqiang Xia, Yiyuan Cui, Bo Jing, Alexander Platero, Yanhui Liu, Yuquan Wei, Paul F Worley, Bo Xiao.

  Neuronal activity increases energy consumption and requires balanced production to maintain neuronal function. How activity is coupled to energy production remains incompletely understood. Here, we report that Rheb regulates mitochondrial tricarboxylic acid cycle flux of acetyl-CoA by activating pyruvate dehydrogenase (PDH) to increase ATP production. Rheb is induced by synaptic activity and lactate and dynamically trafficked to the mitochondrial matrix through its interaction with Tom20. Mitochondria-localized Rheb protein is required for activity-induced PDH activation and ATP production. Cell-type-specific gain- and loss-of-function genetic models for Rheb reveal reciprocal changes in PDH phosphorylation/activity, acetyl-CoA, and ATP that are not evident with genetic or pharmacological manipulations of mTORC1. Mechanistically, Rheb physically associates with PDH phosphatase (PDP), enhancing its activity and association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase its activity. Findings identify Rheb as a nodal point that balances neuronal activity and neuroenergetics via Rheb-PDH axis.

Keywords:  Rheb; mTORC1; mitochondria; neuroenergetics; neuronal activity; pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.devcel.2021.02.022
Cell Metab. 2021 Mar 13. pii: S1550-4131(21)00102-9. [Epub ahead of print]

Excessive exercise training causes mitochondrial functional impairment and decreases glucose tolerance in healthy volunteers.

Mikael Flockhart, Lina C Nilsson, Senna Tais, Björn Ekblom, William Apró, Filip J Larsen.

  Exercise training positively affects metabolic health through increased mitochondrial oxidative capacity and improved glucose regulation and is the first line of treatment in several metabolic diseases. However, the upper limit of the amount of exercise associated with beneficial therapeutic effects has not been clearly identified. Here, we used a training model with a progressively increasing exercise load during an intervention over 4 weeks. We closely followed changes in glucose tolerance, mitochondrial function and dynamics, physical exercise capacity, and whole-body metabolism. Following the week with the highest exercise load, we found a striking reduction in intrinsic mitochondrial function that coincided with a disturbance in glucose tolerance and insulin secretion. We also assessed continuous blood glucose profiles in world-class endurance athletes and found that they had impaired glucose control compared with a matched control group.

Keywords:  athletes; continuous glucose monitoring; exercise; exercise adaptations; glucose tolerance; high-intensity interval training; insulin resistance; metabolic dysfunction; mitochondria; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.cmet.2021.02.017
Nat Aging. 2021 Feb;1(2): 165-178

The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress.

Terytty Yang Li, Maroun Bou Sleiman, Hao Li, Arwen W Gao, Adrienne Mottis, Alexis Maximilien Bachmann, Gaby El Alam, Xiaoxu Li, Ludger J E Goeminne, Kristina Schoonjans, Johan Auwerx.

Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

DOI: https://doi.org/10.1038/s43587-020-00025-z
iScience. 2021 Mar 19. 24(3): 102181

Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response.

Seul Gi Kang, Min Jeong Choi, Saet-Byel Jung, Hyo Kyun Chung, Joon Young Chang, Jung Tae Kim, Yea Eun Kang, Ju Hee Lee, Hyun Jung Hong, Sang Mi Jun, Hyun-Joo Ro, Jae Myoung Suh, Hail Kim, Johan Auwerx, Hyon-Seung Yi, Minho Shong.

  Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.

Keywords:  Cell Biology; Physiology; Systems Biology

DOI:  https://doi.org/10.1016/j.isci.2021.102181
J Biol Chem. 2021 Mar 12. pii: S0021-9258(21)00317-3. [Epub ahead of print] 100539

Choline restores respiration in Psd1-deficient yeast by replenishing mitochondrial phosphatidylethanolamine.

Donna M Iadarola, Alaumy Joshi, Cameron B Caldwell, Vishal M Gohil.

  Phosphatidylethanolamine (PE) is essential for mitochondrial respiration in yeast Saccharomyces cerevisiae, whereas the most abundant mitochondrial phospholipid, phosphatidylcholine (PC), is largely dispensable. Surprisingly, choline (Cho), which is a biosynthetic precursor of PC, has been shown to rescue the respiratory growth of mitochondrial PE deficient yeast; however, the mechanism underlying this rescue has remained unknown. Using a combination of yeast genetics, lipid biochemistry, and cell biological approaches, we uncover the mechanism by showing that Cho rescues mitochondrial respiration by partially replenishing mitochondrial PE levels in yeast cells lacking the mitochondrial PE-biosynthetic enzyme Psd1. This rescue is dependent on the conversion of Cho to PC via the Kennedy pathway as well as on Psd2, an enzyme catalyzing PE biosynthesis in the endosome. Metabolic labeling experiments reveal that in the absence of exogenously supplied Cho, PE biosynthesized via Psd2 is mostly directed to the methylation pathway for PC biosynthesis and is unavailable for replenishing mitochondrial PE in Psd1-deleted cells. In this setting, stimulating the Kennedy pathway for PC biosynthesis by Cho spares Psd2-synthesized PE from the methylation pathway and redirects it to the mitochondria. Cho-mediated elevation in mitochondrial PE is dependent on Vps39, which has been recently implicated in PE trafficking to the mitochondria. Accordingly, epistasis experiments placed Vps39 downstream of Psd2 in choline-based rescue. Our work, thus, provides a mechanism of choline-based rescue of mitochondrial PE deficiency and uncovers an intricate inter-organelle phospholipid regulatory network that maintains mitochondrial PE homeostasis.

Keywords:  Phospholipid; Psd1; Psd2; Vps39; choline; ethanolamine; mitochondria; phosphatidylethanolamine; yeast

DOI:  https://doi.org/10.1016/j.jbc.2021.100539
Open Biol. 2021 Mar;11(3): 210002

The mitochondrial intermembrane space: the most constricted mitochondrial sub-compartment with the largest variety of protein import pathways.

Ruairidh Edwards, Ross Eaglesfield, Kostas Tokatlidis.

  The mitochondrial intermembrane space (IMS) is the most constricted sub-mitochondrial compartment, housing only about 5% of the mitochondrial proteome, and yet is endowed with the largest variability of protein import mechanisms. In this review, we summarize our current knowledge of the major IMS import pathway based on the oxidative protein folding pathway and discuss the stunning variability of other IMS protein import pathways. As IMS-localized proteins only have to cross the outer mitochondrial membrane, they do not require energy sources like ATP hydrolysis in the mitochondrial matrix or the inner membrane electrochemical potential which are critical for import into the matrix or insertion into the inner membrane. We also explore several atypical IMS import pathways that are still not very well understood and are guided by poorly defined or completely unknown targeting peptides. Importantly, many of the IMS proteins are linked to several human diseases, and it is therefore crucial to understand how they reach their normal site of function in the IMS. In the final part of this review, we discuss current understanding of how such IMS protein underpin a large spectrum of human disorders.

Keywords:  intermembrane space; mitochondria; oxidative protein folding; protein import

DOI:  https://doi.org/10.1098/rsob.210002
FEBS Lett. 2021 Mar 20.

Mitochondrial dynamics in health and disease.

Nethmi M B Yapa, Valerie Lisnyak, Boris Reljic, Michael T Ryan.

  In animals, mitochondria are mainly organised into an interconnected tubular network extending across the cell along a cytoskeletal scaffold. Mitochondrial fission and fusion, as well as distribution along cytoskeletal tracks, are counterbalancing mechanisms acting in concert to maintain a mitochondrial network tuned to cellular function. Balanced mitochondrial dynamics permits quality control of the network including biogenesis and turnover, distribution of mtDNA, and are tuned to metabolic status. Cellular and organismal health relies on a delicate balance between fission and fusion and large rearrangements in the mitochondrial network can be seen in response to cellular insults and disease. Indeed, dysfunction in the major components of the fission and fusion machineries including Dynamin-related protein 1 (DRP1), Mitofusins 1 and 2 (MFN1, MFN2) and Optic atrophy protein 1 (OPA1) and ensuing imbalance of mitochondrial dynamics can lead to neurodegenerative disease. Altered mitochondrial dynamics is also seen in more common diseases. In this review, the machinery involved in mitochondrial dynamics and their dysfunction in disease will be discussed.

Keywords:  membrane dynamics; mitochondria; mitochondrial disease; mitochondrial fission; mitochondrial fusion; organelles; oxidative phosphorylation

DOI:  https://doi.org/10.1002/1873-3468.14077