bims-mikwok 2023-10-01 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–10–01
seven papers selected by
Gavin McStay, Liverpool John Moores University

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.
Early fate decision for mitochondrially encoded proteins by a molecular triage.
Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission.
The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.
TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of Mitochondrial integrity and parkin-mediated mitophagy.

Int J Mol Sci. 2023 Sep 08. pii: 13835. [Epub ahead of print]24(18):

Mitochondrial-Derived Vesicles: The Good, the Bad, and the Ugly.

Anna Picca, Flora Guerra, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Cecilia Bucci, Emanuele Marzetti.

  Mitophagy is crucial for maintaining mitochondrial quality. However, its assessment in vivo is challenging. The endosomal-lysosomal system is a more accessible pathway through which subtypes of extracellular vesicles (EVs), which also contain mitochondrial constituents, are released for disposal. The inclusion of mitochondrial components into EVs occurs in the setting of mild mitochondrial damage and during impairment of lysosomal function. By releasing mitochondrial-derived vesicles (MDVs), cells limit the unload of mitochondrial damage-associated molecular patterns with proinflammatory activity. Both positive and negative effects of EVs on recipient cells have been described. Whether this is due to the production of EVs other than those containing mitochondria, such as MDVs, holding specific biological functions is currently unknown. Evidence on the existence of different MDV subtypes has been produced. However, their characterization is not always pursued, which would be relevant to exploring the dynamics of mitochondrial quality control in health and disease. Furthermore, MDV classification may be instrumental in understanding their biological roles and promoting their implementation as biomarkers in clinical studies.

Keywords:  damage-associated molecular patterns (DAMPs); endosomal–lysosomal system; exosomes; extracellular vesicles; inflammation; mitochondrial DNA; mitochondrial quality control; mitophagy; mitovesicles; oxidative stress

DOI:  https://doi.org/10.3390/ijms241813835
Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00696-2. [Epub ahead of print]

Early fate decision for mitochondrially encoded proteins by a molecular triage.

Andreas Kohler, Andreas Carlström, Hendrik Nolte, Verena Kohler, Sung-Jun Jung, Sagar Sridhara, Takashi Tatsuta, Jens Berndtsson, Thomas Langer, Martin Ott.

  Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.

Keywords:  assembly factors; complex assembly; m-AAA protease; mitochondria; mitoribosome; prohibitin; protein biogenesis; protein quality control; respiratory chain; translation

DOI:  https://doi.org/10.1016/j.molcel.2023.09.001
Nat Cell Biol. 2023 Sep 28.

Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.

Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.

DOI: https://doi.org/10.1038/s41556-023-01244-3
ACS Appl Mater Interfaces. 2023 Sep 26.

Programmed Release METTL3-14 Inhibitor Microneedle Protects Myocardial Function by Reducing Drp1 m6A Modification-Mediated Mitochondrial Fission.

Boyue Huang, Liu Xie, Ming Ke, Yonghong Fan, Ju Tan, Jianhua Ran, Chuhong Zhu.

  M6A modification is an RNA-important processing event mediated by methyltransferases METTL3 and METTL14 and the demethylases. M6A dynamic changes after myocardial infarction (MI), involved in the massive loss of cardiomyocytes due to hypoxia, as well as the recruitment and activation of myofibroblasts. Balanced mitochondrial fusion and fission are essential to maintain intracardiac homeostasis and reduce poststress myocardial remodeling. Double-layer programmed drug release microneedle (DPDMN) breaks the limitations of existing therapeutic interventions in one period or one type of cells, and multitargeted cellular combination has more potential in MI therapy. By employing hypoxia-ischemic and TGF-β1-induced fibrosis cell models, we found that METTL3-14 inhibition effectively decreased cardiomyocyte death through the reduction of mitochondrial fragmentation and inhibiting myofibrillar transformation. DPDMN treatment of MI in rat models showed improved cardiac function and decreased infarct size and fibrosis level, demonstrating its superior effectiveness. The DPDMN delivers METTL3 inhibitor swiftly in the early phase to rescue dying cardiomyocytes and slowly in the late phase to achieve long-term suppression of fibroblast over proliferation, collagen synthesis, and deposition. RIP assay and mechanistic investigation confirmed that METTL3 inhibition reduced the translation efficiency of Drp1 mRNA by 5'UTR m6A modification, thus decreasing the Drp1 protein level and mitochondrial fragment after hypoxic-ischemic injury. This project investigated the efficacy of DPDMNs-loaded METTL3 inhibitor in MI treatment and the downstream signaling pathway proteins, providing an experimental foundation for the translation of the utility, safety, and versatility of microneedle drug delivery for MI into clinical applications.

Keywords:  Drp1; METTL3; microneedle; mitochondrial fission; myocardial infarction

DOI:  https://doi.org/10.1021/acsami.3c06318
Protein Sci. 2023 Sep 24. e4787

The variable domain from dynamin-related protein 1 promotes liquid-liquid phase separation that enhances its interaction with cardiolipin-containing membranes.

Ammon E Posey, Kyle A Ross, Mehran Bagheri, Elizabeth N Lanum, Misha A Khan, Christine E Jennings, Megan C Harwig, Nolan W Kennedy, Vincent J Hilser, James L Harden, R Blake Hill.

  Dynamins are an essential superfamily of mechanoenzymes that remodel membranes and often contain a "variable domain" important for regulation. For the mitochondrial fission dynamin, dynamin-related protein 1, a regulatory role for the variable domain is demonstrated by gain- and loss-of-function mutations, yet the basis for this is unclear. Here, the isolated variable domain is shown to be intrinsically disordered and undergo a cooperative transition in the stabilizing osmolyte trimethylamine N-oxide. However, the osmolyte-induced state is not folded and surprisingly appears as a condensed state. Other co-solutes including known molecular crowder Ficoll PM 70, also induce a condensed state. Fluorescence recovery after photobleaching experiments reveal this state to be liquid-like indicating the variable domain undergoes a liquid-liquid phase separation under crowding conditions. These crowding conditions also enhance binding to cardiolipin, a mitochondrial lipid, which appears to promote phase separation. Since dynamin-related protein 1 is found assembled into discrete punctate structures on the mitochondrial surface, the inference from the present work is that these structures might arise from a condensed state involving the variable domain that may enable rapid tuning of mechanoenzyme assembly necessary for fission. This article is protected by copyright. All rights reserved.

Keywords:  NMR; dynamin; fluorescence; intrinsically disordered protein; mitochondria; mitochondrial fission; phase separation; protein folding

DOI:  https://doi.org/10.1002/pro.4787
Nat Commun. 2023 Sep 29. 14(1): 6099

TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.

Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.

Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

DOI: https://doi.org/10.1038/s41467-023-41849-8
J Mol Cell Biol. 2023 Sep 28. pii: mjad056. [Epub ahead of print]

Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of Mitochondrial integrity and parkin-mediated mitophagy.

Yingmei Zhang, Rongjun Zou, Miyesaier Abudureyimu, Qiong Liu, Jipeng Ma, Haixia Xu, Wei Yu, Jian Yang, Jianguo Jia, Sanli Qian, Haichang Wang, Yang Yang, Xin Wang, Xiaoping Fan, Jun Ren.

  Mitochondrial aldehyde dehydrogenase (ALDH2) offers proven cardiovascular benefit although its impact in diabetes remains elusive. This study examined the effect of ALDH2 overexpression (OE) and knockout (KO) on diabetic cardiomyopathy and mechanism involved with a focus on mitochondrial integrity. ALDH2 OE and KO mice were challenged with streptozotocin (STZ, 200 mg/kg. i.p.) to establish diabetes. Diabetic patients displayed reduced plasma ALDH2 activity, cardiac remodeling and diastolic dysfunction. STZ challenge prompted reduced respiratory exchange ratio (RER), dampened fractional shortening, ejection fraction, increased LV end systolic and diastolic diameters, cardiac remodeling, cardiomyocyte contractile and intracellular Ca2+ defects (depressed peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening, dampened intracellular Ca2+ rise and clearance), myocardial ultrastructural injury, oxidative stress, apoptosis and mitochondrial damage, the effects of which were overtly attenuated and accentuated by ALDH2 OE and KO, respectively. Immunoblotting revealed downregulated mitochondrial proteins PPARγ coactivator 1α (PGC-1α) and UCP-2, Ca2+ regulatory proteins including SERCA and Na+-Ca2+ exchanger, elevated phospholamban, dampened autophagy and mitophagy (LC3B ratio, TOM20, Parkin, FUNDC1 and BNIP3), disrupted phosphorylation of Akt, GSK3β and Foxo3a, and elevated PTEN phosphorylation, the effect of which was reversed and worsened by ALDH2 OE and KO, respectively (except FUNDC1 and BNIP3). In vivo and in vitro data revealed that novel ALDH2 activator torezolid/Alda-1 protected against STZ or high glucose-induced cardiac anomalies, the effect was nullified by inhibition of Akt, GSK3β, Parkin and mitochondrial coupling. Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt, GSK3β activation, parkin mitophagy and mitochondrial function.

Keywords:  ALDH2; GSK3β; cardiac contraction; diabetes; mitochondrial function; mitophagy

DOI:  https://doi.org/10.1093/jmcb/mjad056