bims-mecmid 2022-03-27 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–03–27
ten papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.
Insights Into Mitochondrial Dynamics in Chlamydial Infection.
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.
miR-199b-5p-AKAP1-DRP1 pathway plays a key role in ox-LDL-induced mitochondrial fission and endothelial apoptosis.
Mitochondrial dynamics in the neonatal brain - a potential target following injury?
Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway.
Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases.
Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.
Mitochondrial Implications in Cardiovascular Aging and Diseases: The Specific Role of Mitochondrial Dynamics and Shifts.
Nuclear-Mitochondrial Interactions.

Hepatology. 2022 Mar 21.

Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury.

Li Chen, Jun Dong, Siyang Liao, Siyou Wang, Zhida Wu, Meiling Zuo, Bing Liu, Chaojun Yan, Yong Chen, He He, Qingtao Meng, Zhiyin Song.

  Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer- and inner-membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. Here, we show that Sam50 interacts with MICOS and ATAD3 to form the Sam50-MICOS-ATAD3-mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mtDNA aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer- and inner-membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation and release. Physiologically, acetaminophen (APAP, an effective antipyretic and analgesic)-caused Sam50 reduction or Sam50 liver-specific knockout induces mtDNA release, leading to activation of the cGAS-STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP-induced liver hepatoxicity. Thus, our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes, and reveal that Sam50 depletion-induced cardiolipin externalization is a new signal of mtDNA release and controls mtDNA-dependent innate immunity.

Keywords:  Sam50; acetaminophen; cGAS-STING; cardiolipin; mtDNA release

DOI:  https://doi.org/10.1002/hep.32471
Front Cell Infect Microbiol. 2022 ;12 835181

Insights Into Mitochondrial Dynamics in Chlamydial Infection.

Yewei Yang, Wenbo Lei, Lanhua Zhao, Yating Wen, Zhongyu Li.

  Mitochondria are intracellular organelles that are instrumental in the creation of energy, metabolism, apoptosis, and intrinsic immunity. Mitochondria exhibit an extraordinarily high degree of flexibility, and are constantly undergoing dynamic fusion and fission changes. Chlamydia is an intracellular bacterium that causes serious health problems in both humans and animals. Due to a deficiency of multiple metabolic enzymes, these pathogenic bacteria are highly dependent on their eukaryotic host cells, resulting in a close link between Chlamydia infection and host cell mitochondria. Indeed, Chlamydia increase mitochondrial fusion by inhibiting the activation of dynein-related protein 1 (DRP1), which can regulate host cell metabolism for extra energy. Additionally, Chlamydia can inhibit mitochondrial fission by blocking DRP1 oligomerization, preventing host cell apoptosis. These mechanisms are critical for maintaining a favorable environment for reproduction and growth of Chlamydia. This review discusses the molecular mechanisms of mitochondrial fusion and fission, as well as the mechanisms by which Chlamydia infection alters the mitochondrial dynamics and the prospects of limiting chlamydial development by altering mitochondrial dynamics.

Keywords:  ATP; Chlamydia; DRP1; P53; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fcimb.2022.835181
Nat Commun. 2022 Mar 24. 13(1): 1582

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria.

Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A Hay, Craig Blackstone, David C Chan, Robert J Harvey, Ming Guo.

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

DOI: https://doi.org/10.1038/s41467-022-29071-4
Curr Pharm Biotechnol. 2022 Mar 24.

miR-199b-5p-AKAP1-DRP1 pathway plays a key role in ox-LDL-induced mitochondrial fission and endothelial apoptosis.

Xiaolei Cui, Yingping Tian, Yapei Zhao, Hengbo Gao, Dongqi Yao, Liang Liu, Yongjun Li.

   BACKGROUND: Atherosclerosis (AS) remains prevalent despite hyperlipidemia-lowering therapies. Although multiple functions of miR-199b-5p have been implicated in cancers, its role in endothelial apoptosis and AS remains unclear. This study aimed to examine the role of miR-199b-5p in mitochondrial dynamics and endothelial apoptosis.
METHODS: Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were subjected to other treatments, followed by a series analysis. We found that ox-LDL-treated HUVECs were associated with miR-199b-5p downregulation, increased reactive oxygen species level, reduced adenosine triphosphate (ATP) production, mitochondrial fission, and apoptosis, whereas enhanced miR-199b-5p expression or applied mitochondrial division inhibitor 1 (Mdivi-1) markedly reversed these changes.
RESULTS: Mechanistically, A-kinase anchoring protein 1 (AKAP1) was confirmed as a downstream target of miR-199b-5p by dual-luciferase activity reporter assay, AKAP1 overexpression reversed the anti-apoptotic effects of miR-199b-5p through the enhanced interaction of AKAP1 and dynamin protein 1 (DRP1) in ox-LDL-treated HUVECs. Moreover, miR-199b-5p downregulation, AKAP1 upregulation, and excessive mitochondrial fission were verified in human coronary AS endothelial tissues.
CONCLUSION: The miR-199b-5p-dependent regulation of AKAP1/DRP1 is required to inhibit hyperlipidemia-induced mitochondrial fission and endothelial injury and could be a promising therapeutic target for AS.

Keywords:  AKAP1; DRP1; apoptosis; endothelial cell; miR-199b-5p; mitochondrial fission

DOI:  https://doi.org/10.2174/1389201023666220324123224
Biosci Rep. 2022 Mar 31. pii: BSR20211696. [Epub ahead of print]42(3):

Mitochondrial dynamics in the neonatal brain - a potential target following injury?

Adam Jones, Claire Thornton.

  The impact of birth asphyxia and its sequelae, hypoxic-ischaemic (HI) brain injury, is long-lasting and significant, both for the infant and for their family. Treatment options are limited to therapeutic hypothermia, which is not universally successful and is unavailable in low resource settings. The energy deficits that accompany neuronal death following interruption of blood flow to the brain implicate mitochondrial dysfunction. Such HI insults trigger mitochondrial outer membrane permeabilisation leading to release of pro-apoptotic proteins into the cytosol and cell death. More recently, key players in mitochondrial fission and fusion have been identified as targets following HI brain injury. This review aims to provide an introduction to the molecular players and pathways driving mitochondrial dynamics, the regulation of these pathways and how they are altered following HI insult. Finally, we review progress on repurposing or repositioning drugs already approved for other indications, which may target mitochondrial dynamics and provide promising avenues for intervention following brain injury. Such repurposing may provide a mechanism to fast-track, low-cost treatment options to the clinic.

Keywords:  cell death; hypoxia; ischaemia-reperfusion injury; mitochondrial dynamics; neonatal

DOI:  https://doi.org/10.1042/BSR20211696
Free Radic Biol Med. 2022 Mar 19. pii: S0891-5849(22)00107-1. [Epub ahead of print]183 75-88

Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway.

Lang Hu, Yanjie Guo, Liqiang Song, He Wen, Nan Sun, Ying Wang, Bingchao Qi, Qi Liang, Jing Geng, Xuteng Liu, Feng Fu, Yan Li.

  Myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics in patients with diabetes. However, effective strategies to regulate mitochondrial dynamics in the diabetic heart are still lacking. Nicotinamide riboside (NR) supplementation ameliorated mitochondrial dysfunction and oxidative stress in both cardiovascular and aging-related diseases. This study investigated whether NR protects against diabetes-induced cardiac dysfunction by regulating mitochondrial fusion/fission and further explored the underlying mechanisms. Here, we showed an evident decrease in NAD+ (nicotinamide adenine dinucleotide) levels and mitochondrial fragmentation in the hearts of leptin receptor-deficient diabetic (db/db) mouse models. NR supplementation significantly increased NAD+ content in the diabetic hearts and promoted mitochondrial fusion by elevating Mfn2 level. Furthermore, NR-induced mitochondrial fusion suppressed mitochondrial H2O2 and O2•- production and reduced cardiomyocyte apoptosis in both db/db mice hearts and neonatal primary cardiomyocytes. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase reporter assay analyses revealed that PGC1α and PPARα interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1α and promoting the transcription of Mfn2. These findings suggested the promotion of mitochondrial fusion via oral supplementation of NR as a potential strategy for delaying cardiac complications in patients with diabetes.

Keywords:  Diabetic cardiomyopathy; Mfn2; Mitochondrial dynamics; Nicotinamide riboside; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.03.012
Biochem Pharmacol. 2022 Mar 18. pii: S0006-2952(22)00105-8. [Epub ahead of print] 115011

Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases.

Hui Mao, Wei Chen, Linxi Chen, Lanfang Li.

  Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic membrane coupling regions formed by the coupling of the mitochondrial outer membrane and endoplasmic reticulum (ER). MAMs are involved in the mitochondrial dynamics, mitophagy, Ca2+ exchange, and ER stress. A large number of studies indicate that many proteins are involved in the formation of MAMs, including dynamic-related protein 1 (Drp1), DJ-1, PTEN-induced putative kinase 1 (PINK), α-synuclein (α-syn), sigma-1 receptor (S1R), mitofusin-2 (Mfn2), presenilin-1 (PS1), protein kinase R (PKR)-like ER kinase (PERK), Parkin, Cyclophilin D (CypD), glucose-related protein 75 (Grp75), FUN14 domain containing 1 (Fundc1), vesicle-associated membrane-protein-associated protein B (VAPB), phosphofurin acidic cluster sorting protein 2 (PACS-2), ER oxidoreductin 1 (Ero1), and receptor expression-enhancing protein 1 (REEP1). These proteins play an important role in the structure and functions of the MAMs. Abnormalities in these MAM proteins further contribute to the occurrence and development of related diseases, such as neurodegenerative diseases, non-alcoholicfattyliverdisease (NALFD), type 2 diabetes mellitus (T2DM), and diabetic kidney (DN). In this review, we introduce important proteins involved in the structure and the functions of the MAMs. Furthermore, we effectively summarize major insights about these proteins that are involved in the physiopathology of several diseases through the effect on MAMs.

Keywords:  Mitochondria-associated endoplasmic reticulum membranes; diabetic kidney; neurodegenerative diseases; non-alcoholic fatty liver disease; type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.bcp.2022.115011
iScience. 2022 Apr 15. 25(4): 103996

Prevention and regression of megamitochondria and steatosis by blocking mitochondrial fusion in the liver.

Tatsuya Yamada, Daisuke Murata, David E Kleiner, Robert Anders, Avi Z Rosenberg, Jeffrey Kaplan, James P Hamilton, Mariam Aghajan, Moshe Levi, Nae-Yuh Wang, Ted M Dawson, Toru Yanagawa, Andrew F Powers, Miho Iijima, Hiromi Sesaki.

  Non-alcoholic steatohepatitis (NASH) is a most common chronic liver disease that is manifested by steatosis, inflammation, fibrosis, and tissue damage. Hepatocytes produce giant mitochondria termed megamitochondria in patients with NASH. It has been shown that gene knockout of OPA1, a mitochondrial dynamin-related GTPase that mediates mitochondrial fusion, prevents megamitochondria formation and liver damage in a NASH mouse model induced by a methionine-choline-deficient (MCD) diet. However, it is unknown whether blocking mitochondrial fusion mitigates NASH pathologies. Here, we acutely depleted OPA1 using antisense oligonucleotides in the NASH mouse model before or after megamitochondria formation. When OPA1 ASOs were applied at the disease onset, they effectively prevented megamitochondria formation and liver pathologies in the MCD model. Notably, even when applied after mice robustly developed NASH pathologies, OPA1 targeting effectively regressed megamitochondria and the disease phenotypes. Thus, our data show the efficacy of mitochondrial dynamics as a unique therapy for megamitochondria-associated liver disease.

Keywords:  Cell biology; Hepatology

DOI:  https://doi.org/10.1016/j.isci.2022.103996
Int J Mol Sci. 2022 Mar 09. pii: 2951. [Epub ahead of print]23(6):

Mitochondrial Implications in Cardiovascular Aging and Diseases: The Specific Role of Mitochondrial Dynamics and Shifts.

Anastasia V Poznyak, Tatiana V Kirichenko, Evgeny E Borisov, Nikolay K Shakhpazyan, Andrey G Kartuesov, Alexander N Orekhov.

  Cardiovascular disease has been, and remains, one of the leading causes of death in the modern world. The elderly are a particularly vulnerable group. The aging of the body is inevitably accompanied by the aging of all its systems, and the cardiovascular system is no exception. The aging of the cardiovascular system is a significant risk factor for the development of various diseases and pathologies, from atherosclerosis to ischemic stroke. Mitochondria, being the main supplier of energy necessary for the normal functioning of cells, play an important role in the proper functioning of the cardiovascular system. The functioning of each individual cell and the organism as a whole depends on their number, structure, and performance, as well as the correct operation of the system in removing non-functional mitochondria. In this review, we examine the role of mitochondria in the aging of the cardiovascular system, as well as in diseases (for example, atherosclerosis and ischemic stroke). We pay special attention to changes in mitochondrial dynamics since the shift in the balance between fission and fusion is one of the main factors associated with various cardiovascular pathologies.

Keywords:  atherosclerosis; cardiovascular disease; ischemic stroke; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/ijms23062951
Biomolecules. 2022 Mar 10. pii: 427. [Epub ahead of print]12(3):

Nuclear-Mitochondrial Interactions.

Brittni R Walker, Carlos T Moraes.

  Mitochondria, the cell's major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship.

Keywords:  MAMs; integrated stress response; mitochondria; nucleus; retrograde signaling

DOI:  https://doi.org/10.3390/biom12030427