bims-mitdyn 2023-11-12 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2023‒11‒12
fifteen papers selected by
Edmond Chan, Queen’s University, School of Medicine

Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.
Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.
Sperm bud mitochondria to adjust the numbers.
Membrane contact site detection (MCS-DETECT) reveals dual control of rough mitochondria-ER contacts.
Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.
Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.
Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria.
Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK.
ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.
Mitohormesis.
FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.
SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.
The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.

EMBO J. 2023 Nov 07. e114054

Cristae formation is a mechanical buckling event controlled by the inner mitochondrial membrane lipidome.

Kailash Venkatraman, Christopher T Lee, Guadalupe C Garcia, Arijit Mahapatra, Daniel Milshteyn, Guy Perkins, Keun-Young Kim, H Amalia Pasolli, Sebastien Phan, Jennifer Lippincott-Schwartz, Mark H Ellisman, Padmini Rangamani, Itay Budin.

  Cristae are high-curvature structures in the inner mitochondrial membrane (IMM) that are crucial for ATP production. While cristae-shaping proteins have been defined, analogous lipid-based mechanisms have yet to be elucidated. Here, we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions dictate IMM morphology and ATP generation. When modulating phospholipid (PL) saturation in engineered yeast strains, we observed a surprisingly abrupt breakpoint in IMM topology driven by a continuous loss of ATP synthase organization at cristae ridges. We found that cardiolipin (CL) specifically buffers the inner mitochondrial membrane against curvature loss, an effect that is independent of ATP synthase dimerization. To explain this interaction, we developed a continuum model for cristae tubule formation that integrates both lipid and protein-mediated curvatures. This model highlighted a snapthrough instability, which drives IMM collapse upon small changes in membrane properties. We also showed that cardiolipin is essential in low-oxygen conditions that promote PL saturation. These results demonstrate that the mechanical function of cardiolipin is dependent on the surrounding lipid and protein components of the IMM.

Keywords:  cardiolipin; cristae; lipids; mechanics; mitochondria

DOI:  https://doi.org/10.15252/embj.2023114054
Nat Cell Biol. 2023 Nov;25(11): 1625-1636

Mitopherogenesis, a form of mitochondria-specific ectocytosis, regulates sperm mitochondrial quantity and fertility.

Peng Liu, Jing Shi, Danli Sheng, Wenqing Lu, Jie Guo, Lei Gao, Xiaoqing Wang, Shaofeng Wu, Yanwen Feng, Dashan Dong, Xiaoshuai Huang, Hongyun Tang.

Mitochondrial export into the extracellular space is emerging as a fundamental cellular process implicated in diverse physiological activities. Although a few studies have shed light on the process of discarding damaged mitochondria, how mitochondria are exported and the functions of mitochondrial release remain largely unclear. Here we describe mitopherogenesis, a formerly unknown process that specifically secretes mitochondria through a unique extracellular vesicle termed a 'mitopher'. We observed that during sperm development in male Caenorhabditis elegans, healthy mitochondria are exported out of the spermatids through mitopherogenesis and each of the generated mitophers harbours only one mitochondrion. In mitopherogenesis, the plasma membrane first forms mitochondrion-embedding outward buds, which then promptly bud off and thereby result in the generation of mitophers. Mechanistically, extracellular protease signalling in the testis triggers mitopher formation from spermatids, which is partially mediated by the tyrosine kinase SPE-8. Moreover, mitopherogenesis requires normal microfilament dynamics, whereas myosin VI antagonizes mitopher generation. Strikingly, our three-dimensional electron microscopy analyses indicate that mitochondrial quantity requires precise modulation during sperm development, which is critically mediated by mitopherogenesis. Inhibition of mitopherogenesis causes accumulation of mitochondria in sperm, which may lead to sperm motility and fertility defects. Our findings identify mitopherogenesis as a previously undescribed process for mitochondria-specific ectocytosis, which may represent a fundamental branch of mechanisms underlying mitochondrial quantity control to regulate cell functions during development.

DOI: https://doi.org/10.1038/s41556-023-01264-z
Nat Cell Biol. 2023 Nov;25(11): 1564-1565

Sperm bud mitochondria to adjust the numbers.

Diane C Shakes.

DOI: https://doi.org/10.1038/s41556-023-01255-0
J Cell Biol. 2024 Jan 01. pii: e202206109. [Epub ahead of print]223(1):

Membrane contact site detection (MCS-DETECT) reveals dual control of rough mitochondria-ER contacts.

Ben Cardoen, Kurt R Vandevoorde, Guang Gao, Milene Ortiz-Silva, Parsa Alan, William Liu, Ellie Tiliakou, A Wayne Vogl, Ghassan Hamarneh, Ivan R Nabi.

Identification and morphological analysis of mitochondria-ER contacts (MERCs) by fluorescent microscopy is limited by subpixel resolution interorganelle distances. Here, the membrane contact site (MCS) detection algorithm, MCS-DETECT, reconstructs subpixel resolution MERCs from 3D super-resolution image volumes. MCS-DETECT shows that elongated ribosome-studded riboMERCs, present in HT-1080 but not COS-7 cells, are morphologically distinct from smaller smooth contacts and larger contacts induced by mitochondria-ER linker expression in COS-7 cells. RiboMERC formation is associated with increased mitochondrial potential, reduced in Gp78 knockout HT-1080 cells and induced by Gp78 ubiquitin ligase activity in COS-7 and HeLa cells. Knockdown of riboMERC tether RRBP1 eliminates riboMERCs in both wild-type and Gp78 knockout HT-1080 cells. By MCS-DETECT, Gp78-dependent riboMERCs present complex tubular shapes that intercalate between and contact multiple mitochondria. MCS-DETECT of 3D whole-cell super-resolution image volumes, therefore, identifies novel dual control of tubular riboMERCs, whose formation is dependent on RRBP1 and size modulated by Gp78 E3 ubiquitin ligase activity.

DOI: https://doi.org/10.1083/jcb.202206109
Immunity. 2023 Oct 31. pii: S1074-7613(23)00444-2. [Epub ahead of print]

Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.

Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman.

  Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.

Keywords:  CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis

DOI:  https://doi.org/10.1016/j.immuni.2023.10.004
Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00367-7. [Epub ahead of print]

Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.

Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.

  The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.

Keywords:  ISR; UPR; integrated stress response; pharmacologic activator; stress-responsive signaling pathway; unfolded protein response

DOI:  https://doi.org/10.1016/j.chembiol.2023.10.006
Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00441-X. [Epub ahead of print] 101264

Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.

Tao Xing, Li Li, Yiran Chen, Gaoda Ju, Guilan Li, Xiaoyun Zhu, Yubo Ren, Jing Zhao, Zhilei Cheng, Yan Li, Da Xu, Jun Liang.

ARID1A is among the most commonly mutated tumor suppressor genes in hepatocellular carcinoma (HCC). In this study, we conduct a CRISPR-Cas9 synthetic lethality screen using ARID1A-deficient HCC cells to identify approaches to treat HCC patients harboring ARID1A deficiency. This strategy reveals that the survival of these ARID1A-deficient HCC cells is highly dependent on genes related to the tricarboxylic acid (TCA) cycle. Mechanistically, ARID1A loss represses expression of key glycolysis-related gene PKM, shifting cellular glucose metabolism from aerobic glycolysis to dependence on the TCA cycle and oxidative phosphorylation. Cuproptosis is a recently defined form of copper-induced cell death reported to directly target the TCA cycle. Here, we find that ARID1A-deficient HCC cells and xenograft tumors are highly sensitive to copper treatment. Together, these results offer evidence of the synthetic lethality between ARID1A deficiency and mitochondrial respiration impairment, suggesting that copper treatment constitutes a promising therapeutic strategy for selectively targeting ARID1A-deficient HCC.

DOI: https://doi.org/10.1016/j.xcrm.2023.101264
Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00442-1. [Epub ahead of print] 101265

Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.

Hanneke L D M Willemen, Patrícia Silva Santos Ribeiro, Melissa Broeks, Nils Meijer, Sabine Versteeg, Annefien Tiggeler, Teun P de Boer, Jędrzej M Małecki, Pål Ø Falnes, Judith Jans, Niels Eijkelkamp.

  Pain often persists in patients with an inflammatory disease, even when inflammation has subsided. The molecular mechanisms leading to this failure in pain resolution and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons links to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of pain induced by a subsequent inflammatory stimulus. We identify that hyperalgesic priming in mice increases the expression of a mitochondrial protein (ATPSc-KMT) and causes mitochondrial and metabolic disturbances in sensory neurons. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or supplementation of the affected metabolite is sufficient to restore resolution of inflammatory pain and prevents chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in sensory neurons predispose to a failure in resolution of inflammatory pain and development of chronic pain.

Keywords:  chronic pain; inflammation; metabolism; mitochondria; redox; sensory neurons

DOI:  https://doi.org/10.1016/j.xcrm.2023.101265
Cell Rep. 2023 Nov 04. pii: S2211-1247(23)01401-8. [Epub ahead of print]42(11): 113389

Hepatic palmitoyl-proteomes and acyl-protein thioesterase protein proximity networks link lipid modification and mitochondria.

Sarah L Speck, Dhaval P Bhatt, Qiang Zhang, Sangeeta Adak, Li Yin, Guifang Dong, Chu Feng, Wei Zhang, M Ben Major, Xiaochao Wei, Clay F Semenkovich.

  Acyl-protein thioesterases 1 and 2 (APT1 and APT2) reverse S-acylation, a potential regulator of systemic glucose metabolism in mammals. Palmitoylation proteomics in liver-specific knockout mice shows that APT1 predominates over APT2, primarily depalmitoylating mitochondrial proteins, including proteins linked to glutamine metabolism. miniTurbo-facilitated determination of the protein-protein proximity network of APT1 and APT2 in HepG2 cells reveals APT proximity networks encompassing mitochondrial proteins including the major translocases Tomm20 and Timm44. APT1 also interacts with Slc1a5 (ASCT2), the only glutamine transporter known to localize to mitochondria. High-fat-diet-fed male mice with dual (but not single) hepatic deletion of APT1 and APT2 have insulin resistance, fasting hyperglycemia, increased glutamine-driven gluconeogenesis, and decreased liver mass. These data suggest that APT1 and APT2 regulation of hepatic glucose metabolism and insulin signaling is functionally redundant. Identification of substrates and protein-protein proximity networks for APT1 and APT2 establishes a framework for defining mechanisms underlying metabolic disease.

Keywords:  CP: Metabolism; acyl-protein thioesterase 1; acyl-protein thioesterase 2; gluconeogenesis; glutamine; insulin; liver; palmitoylation; proximity labeling

DOI:  https://doi.org/10.1016/j.celrep.2023.113389
J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02469-9. [Epub ahead of print] 105441

Interaction between the mitochondrial adaptor MIRO and the motor adaptor TRAK.

Elana E Baltrusaitis, Erika E Ravitch, Adam R Fenton, Tania Perez, Erika L F Holzbaur, Roberto Dominguez.

  MIRO (mitochondrial Rho GTPase) consists of two GTPase domains flanking two Ca2+-binding EF-hand domains. A C-terminal transmembrane helix anchors MIRO to the outer mitochondrial membrane, where it functions as a general adaptor for the recruitment of cytoskeletal proteins that control mitochondrial dynamics. One protein recruited by MIRO is TRAK (trafficking kinesin-binding protein), which in turn recruits the microtubule-based motors kinesin-1 and dynein-dynactin. The mechanism by which MIRO interacts with TRAK on the mitochondrial membrane is not well understood. Here, we map and quantitatively characterize the interaction of human MIRO1 and TRAK1 and test its potential regulation by Ca2+ and/or GTP binding to MIRO1. TRAK1 binds MIRO1 with low micromolar affinity. The interaction was mapped to a fragment comprising MIRO1's EF-hands and C-terminal GTPase domain and to a conserved sequence motif within TRAK1 residues 394-431, immediately C-terminal to the Spindly motif. This sequence is sufficient for MIRO1 binding in vitro and is necessary for MIRO1-dependent localization of TRAK1 to mitochondria in cells. MIRO1's EF-hands bind Ca2+ with dissociation constants (KD) of 3.9 μM and 300 nM. This suggests that under cellular conditions one EF-hand may be constitutively bound to Ca2+ whereas the other EF-hand binds Ca2+ in a regulated manner, depending on its local concentration. Yet, the MIRO1-TRAK1 interaction is independent of Ca2+ binding to the EF-hands and of the nucleotide state (GDP or GTP) of the C-terminal GTPase. The interaction is also independent of TRAK1 dimerization, such that a TRAK1 dimer can be expected to bind two MIRO1 molecules on the mitochondrial surface.

Keywords:  EF-hand; GTPase; Mitochondrial dynamics; calcium; isothermal titration calorimetry (ITC); motor adaptor; mutagenesis

DOI:  https://doi.org/10.1016/j.jbc.2023.105441
Life Sci Alliance. 2024 Jan;pii: e202302335. [Epub ahead of print]7(1):

ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis.

Alexandre Janer, Jordan L Morris, Michiel Krols, Hana Antonicka, Mari J Aaltonen, Zhen-Yuan Lin, Hanish Anand, Anne-Claude Gingras, Julien Prudent, Eric A Shoubridge.

Mitochondria interact with the ER at structurally and functionally specialized membrane contact sites known as mitochondria-ER contact sites (MERCs). Combining proximity labelling (BioID), co-immunoprecipitation, confocal microscopy and subcellular fractionation, we found that the ER resident SMP-domain protein ESYT1 was enriched at MERCs, where it forms a complex with the outer mitochondrial membrane protein SYNJ2BP. BioID analyses using ER-targeted, outer mitochondrial membrane-targeted, and MERC-targeted baits, confirmed the presence of this complex at MERCs and the specificity of the interaction. Deletion of ESYT1 or SYNJ2BP reduced the number and length of MERCs. Loss of the ESYT1-SYNJ2BP complex impaired ER to mitochondria calcium flux and provoked a significant alteration of the mitochondrial lipidome, most prominently a reduction of cardiolipins and phosphatidylethanolamines. Both phenotypes were rescued by reexpression of WT ESYT1 and an artificial mitochondria-ER tether. Together, these results reveal a novel function for ESYT1 in mitochondrial and cellular homeostasis through its role in the regulation of MERCs.

DOI: https://doi.org/10.26508/lsa.202302335
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00380-7. [Epub ahead of print]35(11): 1872-1886

Mitohormesis.

Yu-Wei Cheng, Jie Liu, Toren Finkel.

Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.

DOI: https://doi.org/10.1016/j.cmet.2023.10.011
Biochem Biophys Res Commun. 2023 Nov 01. pii: S0006-291X(23)01304-9. [Epub ahead of print]687 149210

FUNDC1 collaborates with PINK1 in regulating mitochondrial Fission and compensating for PINK1 deficiency.

Jing Xu, Zhouyang Deng, Shuai Shang, Caifang Wang, Hailong Han.

  Parkinson's disease is presently thought to have its molecular roots in the alteration of PINK1-mediated mitophagy and mitochondrial dynamics. Finding new suppressors of the pathway is essential for developing cutting-edge treatment approaches. Our study shows that FUNDC1 suppressed PINK1 mutant phenotypes in Drosophila. The restoration of PINK1-deficient phenotypes through FUNDC1 is not reliant on its LC3-binding motif Y (18)L (21) or autophagy-related pathway. Moreover, the absence of Drp1 affects the phenotypic restoration of PINK1 mediated by FUNDC1 in flies. In summary, our findings have unveiled a fresh mechanism through which FUNDC1 compensates for the loss of PINK1, operating independently of autophagy but exerting its influence via interaction with Drp1.

Keywords:  Autophagy receptor; Drp1; Mitochondrial dynamics; PD; Ubiquitin-independent mitophagy

DOI:  https://doi.org/10.1016/j.bbrc.2023.149210
Cell Death Dis. 2023 Nov 10. 14(11): 732

SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.

Srimanta Patra, Amruta Singh, Prakash P Praharaj, Nitish K Mohanta, Mrutyunjay Jena, Birija S Patro, Ali Abusharha, Shankargouda Patil, Sujit K Bhutia.

SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orchestrates inhibition of DNM1L-mediated mitochondrial fission, subsequently leading to the formation of hyperfused mitochondrial networks. The hyperfused mitochondrial networks preserve the release of cytochrome C (CYCS) by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoid clustering mimicking mito-bulb like structures) and reducing the generation of mitochondrial superoxide to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-regulated mitochondrial fission. In the overexpressed cells, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of CYCS along with an enhanced generation of mitochondrial superoxide for the subsequent induction of apoptosis. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, nullifies CDDP-mediated apoptosis inhibition by suppressing mitochondrial hyperfusion. In this setting, SIRT1 knockdown hinders apoptosis activation in GA-primed oral cancer cells. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer-derived polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Interestingly, synergistically treated with CDDP, GA induces apoptosis in the PGCCs by inhibiting mitochondrial hyperfusion.

DOI: https://doi.org/10.1038/s41419-023-06232-x
Cardiovasc Res. 2023 Oct 31. pii: cvad169. [Epub ahead of print]

The inhibition of inner mitochondrial fusion in hepatocytes reduces NAFL and improves metabolic profile during obesity by modulating bile acid conjugation.

Lorenzo Da Dalt, Annalisa Moregola, Monika Svecla, Silvia Pedretti, Francesca Fantini, Mirko Ronzio, Patrizia Uboldi, Diletta Dolfini, Elena Donetti, Andrea Baragetti, Nico Mitro, Luca Scorrano, Giuseppe Danilo Norata.

  BACKGROUND AND AIM: Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols and bile acids (BAs) synthesis. Here we evaluated how the impairment of mitochondrial fusion in hepatocytes affect diet induced liver steatosis and obesity.METHODS AND RESULTS: Male mice selectively lacking the key protein involved in inner mitochondrial fusion, OPA1, (OPA1ΔHep) on a High Fat Diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from the development of hepatic steatosis and obesity because of reduced lipid absorption; a profile which was accompanied by increased respiratory exchange ratio in vivo, suggesting a preference for carbohydrate in OPA1ΔHep in agreement with the defect in mitochondrial fusion. At the molecular level, this phenotype emerged as a consequence of poor mitochondrial-peroxisome-ER tethering in OPA1 deficient hepatocytes thus impairing bile acid conjugation and therefore its release in the bile, thus impacting lipid absorption from the diet. Concordantly the liver of NAFLD subjects presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial when compared to controls.
CONCLUSION: Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective inhibition of liver mitochondrial fusion observed in hepatocyte OPA1 deficient mice protects mice from HFD-induced metabolic dysfunction by reducing lipid dietary absorption and bile acid secretion as a consequence of reduced liver mitochondria-peroxisome-ER tethering.

Keywords:  Bile Acids; Dietary Lipid Absorption; Liver; Mitochondria

DOI:  https://doi.org/10.1093/cvr/cvad169