bims-mikwok 2023-01-01 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒01‒01
thirteen papers selected by
Avinash N. Mukkala, University of Toronto

Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.
Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.
Mitochondria and peroxisomes: partners in autophagy.
ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation.
Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.
How does density of the inner mitochondrial membrane influence mitochondrial performance?
Mitochondrial dynamics, elimination and biogenesis during post-ischemic recovery in ischemia-resistant and ischemia-vulnerable gerbil hippocampal regions.
DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.
The impact of high fat feeding and Parkin overexpression on skeletal muscle mass, mitochondrial respiration and H2O2 emission.
Doxorubicin induces cardiomyocyte death owing to the accumulation of dysfunctional mitochondria by inhibiting the autophagy fusion process.
Transgenic type2 diabetes mouse models for in vivo redox measurement of hepatic mitochondrial oxidative stress.
Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.

J Biol Chem. 2022 Dec 22. pii: S0021-9258(22)01268-6. [Epub ahead of print] 102825

Mitochondria-localized lncRNA HITT inhibits fusion by attenuating formation of mitofusin-2 homo- or heterotypic complexes.

Xingwen Wang, Yi Zhang, Qingyu Lin, Kunming Zhao, Dantong Zhu, Ying Hu.

  Long non-coding RNAs (lncRNAs) are emerging as essential players in multiple biological processes. Mitochondrial dynamics, comprising the continuous cycle of fission and fusion, are required for healthy mitochondria that function properly. Despite long-term recognition of its significance in cell-fate control, the mechanism underlying mitochondrial fusion is not completely understood, particularly regarding the involvement of lncRNAs. Here, we show that the lncRNA HITT (HIF-1α inhibitor at translation level), can specifically localize in mitochondria. Cells expressing higher levels of HITT contain fragmented mitochondria. Conversely, we show that HITT knockdown cells have more tubular mitochondria than is present in control cells. Mechanistically, we demonstrate HITT directly binds mitofusin-2 (MFN2), a core component that mediates mitochondrial outer membrane fusion, by the in vitro RNA pull-down and UV-cross-linking RNA-IP (CLIP) assays. In doing so, we found HITT disturbs MFN2 homo- or heterotypic complex formation, attenuating mitochondrial fusion. Under stress conditions, such as ultraviolet radiation, we in addition show HITT stability increases as a consequence of MiR-205 downregulation, inhibiting MFN2-mediated fusion and leading to apoptosis. Overall, our data provide significant insights into the roles of organelle (mitochondria)-specific resident lncRNAs in regulating mitochondrial fusion, and also reveal how such a mechanism controls cellular sensitivity to UV radiation-induced apoptosis.

Keywords:  LINC00637; MFN2; apoptosis; mitochondrial dynamics; mitochondrial fusion

DOI:  https://doi.org/10.1016/j.jbc.2022.102825
Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01771-5. [Epub ahead of print]41(13): 111875

Mitochondrial genome recovery by ATFS-1 is essential for development after starvation.

Nandhitha Uma Naresh, Sookyung Kim, Tomer Shpilka, Qiyuan Yang, Yunguang Du, Cole M Haynes.

  Nutrient availability regulates the C. elegans life cycle as well as mitochondrial physiology. Food deprivation significantly reduces mitochondrial genome (mtDNA) numbers and leads to aging-related phenotypes. Here we show that the bZIP (basic leucine zipper) protein ATFS-1, a mediator of the mitochondrial unfolded protein response (UPRmt), is required to promote growth and establish a functional germline after prolonged starvation. We find that recovery of mtDNA copy numbers and development after starvation requires mitochondrion-localized ATFS-1 but not its nuclear transcription activity. We also find that the insulin-like receptor DAF-2 functions upstream of ATFS-1 to modulate mtDNA content. We show that reducing DAF-2 activity represses ATFS-1 nuclear function while causing an increase in mtDNA content, partly mediated by mitochondrion-localized ATFS-1. Our data indicate the importance of the UPRmt in recovering mitochondrial mass and suggest that atfs-1-dependent mtDNA replication precedes mitochondrial network expansion after starvation.

Keywords:  ATFS-1; C. elegans; CP: Metabolism; CP: Molecular biology; DAF-2; UPR; UPRmt; insulin receptor; mitochondria; mtDNA; starvation; stress response

DOI:  https://doi.org/10.1016/j.celrep.2022.111875
Autophagy. 2022 Dec 26. 1-2

Mitochondria and peroxisomes: partners in autophagy.

Léa P Wilhelm, Ian G Ganley.

  Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.

Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy

DOI:  https://doi.org/10.1080/15548627.2022.2155368
Pharmacol Res. 2022 Dec 21. pii: S1043-6618(22)00554-0. [Epub ahead of print]187 106608

ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation.

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

  Mitochondrial metabolism plays a pivotal role in various cellular processes and fibrosis. However, the mechanism underlying mitochondrial metabolic function and liver fibrosis remains poorly understood. In this study, we determined whether mitochondrial metabolism mediates liver fibrosis using cells, animal models, and clinical samples to elucidate the potential effects and underlying mechanism of mitochondrial metabolism in liver fibrosis. We report that AlkB Homolog 5 (ALKBH5) decreases mitochondrial membrane potential (MMP) and oxygen consumption rate (OCR), suppresses mitochondrial fission and hepatic stellate cell (HSC) proliferation and migration and ameliorates liver fibrosis. Enhancement of mitochondrial fission, an essential event during HSC proliferation and migration, is dependent on decreased ALKBH5 expression. Furthermore, we reveal that low ALKBH5 expression is associated with elevated N6-methyladenosine (m6A) mRNA levels. Mechanistically, ALKBH5 mediates m6A demethylation in the 3'UTR of Drp1 mRNA and induces its translation in a YTH domain family proteins 1 (YTHDF1)-independent manner. Subsequently, in transforming growth factor-β1 (TGF-β1) induced HSC, Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and increases cell proliferation and migration. Decreased Drp1 expression inhibits mitochondrial fission and suppresses HSC proliferation and migration. Notably, human fibrotic liver and heart tissue exhibited enhanced mitochondrial fission; increased YTHDF1, Drp1, alpha-smooth muscle actin (α-SMA) and collagen I expression; decreased ALKBH5 expression and increased liver fibrosis. Our results highlight a novel mechanism by which ALKBH5 suppresses mitochondrial fission and HSC proliferation and migration by reducing Drp1 methylation in an m6A-YTHDF1-dependent manner, which may indicate a demethylation-based approach for liver fibrosis diagnosis and therapy.

Keywords:  ALKBH5; Drp1; Hepatic stellate cells; Liver fibrosis; Mitochondrial fission; YTHDF1

DOI:  https://doi.org/10.1016/j.phrs.2022.106608
Curr Opin Cell Biol. 2022 Dec 27. pii: S0955-0674(22)00103-X. [Epub ahead of print]80 102150

Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.

Nida Ul Fatima, Vaishnavi Ananthanarayanan.

  Mitochondria are highly dynamic organelles that undergo rapid morphological adaptations influencing their number, transport, cellular distribution, and function, which in turn facilitate the integration of mitochondrial function with physiological changes in the cell. These mitochondrial dynamics are dependent on tightly regulated processes such as fission, fusion, and attachment to the cytoskeleton, and their defects are observed in various pathophysiological conditions including cancer, cardiovascular disease, and neurodegeneration. Various studies over the years have identified key molecular players and uncovered the mechanisms that mediate and regulate these processes and have highlighted their complexity and context-specificity. This review focuses on the recent studies that have contributed to the understanding of processes that influence mitochondrial morphology including fission, fusion, and transport in the cell.

Keywords:  Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial transport

DOI:  https://doi.org/10.1016/j.ceb.2022.102150
Am J Physiol Regul Integr Comp Physiol. 2022 Dec 26.

How does density of the inner mitochondrial membrane influence mitochondrial performance?

Kyle B Heine, Hailey A Parry, Wendy R Hood.

  Our current understanding of variation in mitochondrial performance is incomplete. The production of ATP via oxidative phosphorylation is dependent, in part, upon the structure of the inner mitochondrial membrane. Morphology of the inner membrane is crucial for the formation of the proton gradient across the inner membrane and, therefore, ATP synthesis. The inner mitochondrial membrane is dynamic, changing shape and surface area. These changes alter density (amount per volume) of the inner mitochondrial membrane within the confined space of the mitochondrion. Because the number of electron transport system proteins within the inner mitochondrial membrane changes with inner mitochondrial membrane area, a change in the amount of inner membrane alters the capacity for ATP production within the organelle. This review outlines the evidence that the association between ATP synthases, inner mitochondrial membrane density, and mitochondrial density (number of mitochondria per cell), impact ATP production by mitochondria. Further, we consider possible constraints on the capacity of mitochondria to produce ATP by increasing inner mitochondrial membrane density.

Keywords:  ATP synthase; cristae; inter-membrane space; matrix; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpregu.00254.2022
Biochim Biophys Acta Mol Basis Dis. 2022 Dec 22. pii: S0925-4439(22)00304-0. [Epub ahead of print]1869(3): 166633

Mitochondrial dynamics, elimination and biogenesis during post-ischemic recovery in ischemia-resistant and ischemia-vulnerable gerbil hippocampal regions.

Maria Kawalec, Piotr Wojtyniak, Ewelina Bielska, Anita Lewczuk, Anna Boratyńska-Jasińska, Małgorzata Beręsewicz-Haller, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Barbara Zabłocka.

  Transient ischemic attacks (TIA) result from a temporary blockage in blood circulation in the brain. As TIAs cause disabilities and often precede full-scale strokes, the effects of TIA are investigated to develop neuroprotective therapies. We analyzed changes in mitochondrial network dynamics, mitophagy and biogenesis in sections of gerbil hippocampus characterized by a different neuronal survival rate after 5-minute ischemia-reperfusion (I/R) insult. Our research revealed a significantly greater mtDNA/nDNA ratio in CA2-3, DG hippocampal regions (5.8 ± 1.4 vs 3.6 ± 0.8 in CA1) that corresponded to a neuronal resistance to I/R. During reperfusion, an increase of pro-fission (phospho-Ser616-Drp1/Drp1) and pro-fusion proteins (1.6 ± 0.5 and 1.4 ± 0.3 for Mfn2 and Opa1, respectively) was observed in CA2-3, DG. Selective autophagy markers, PINK1 and SQSTM1/p62, were elevated 24-96 h after I/R and accompanied by significant elevation of transcription factors proteins PGC-1α and Nrf1 (1.2 ± 0.4, 1.78 ± 0.6, respectively) and increased respiratory chain proteins (e.g., 1.5 ± 0.3 for complex IV at I/R 96 h). Contrastingly, decreased enzymatic activity of citrate synthase, reduced Hsp60 protein level and electron transport chain subunits (0.88 ± 0.03, 0.74 ± 0.1 and 0.71 ± 0.1 for complex IV at I/R 96 h, respectively) were observed in I/R-vulnerable CA1. The phospho-Ser616-Drp1/Drp1 was increased while Mfn2 and total Opa1 reduced to 0.88 ± 0.1 and 0.77 ± 0.17, respectively. General autophagy, measured as LC3-II/I ratio, was activated 3 h after reperfusion reaching 2.37 ± 0.9 of control. This study demonstrated that enhanced mitochondrial fusion, followed by late and selective mitophagy and mitochondrial biogenesis might together contribute to reduced susceptibility to TIA.

Keywords:  Autophagy; Electron transport chain; Mitochondrial biogenesis; Mitophagy; Transient brain ischemia; hippocampus; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2022.166633
Nucleic Acids Res. 2022 Dec 30. pii: gkac1214. [Epub ahead of print]

DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).

Wenyan Xu, Jin Tang, Linlin Zhao.

In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA-protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3'-phospho-α,β-unsaturated aldehyde (3'pUA) residue on SSB. The 3'pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3'pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA.

DOI: https://doi.org/10.1093/nar/gkac1214
J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01280-7. [Epub ahead of print] 102837

Mitochondria directly sense osmotic stress to trigger rapid metabolic remodeling via regulation of pyruvate dehydrogenase (PDH) phosphorylation.

Takeshi Ikizawa, Kazutaka Ikeda, Makoto Arita, Shojiro Kitajima, Tomoyoshi Soga, Hidenori Ichijo, Isao Naguro.

  A high-salt diet significantly impacts various diseases, including cancer and immune diseases. Recent studies suggest that the high-salt/hyperosmotic environment in the body may alter the chronic properties of cancer and immune cells in the disease context. However, little is known about the acute metabolic changes in hyperosmotic stress. Here, we found that hyperosmotic stress for a few minutes induces Warburg-like metabolic remodeling in HeLa and Raw264.7 cells and suppresses fatty acid oxidation. Regarding Warburg-like remodeling, we determined that the pyruvate dehydrogenase (PDH) phosphorylation status was altered bidirectionally (high in hyperosmolarity and low in hypoosmolarity) to osmotic stress in isolated mitochondria, suggesting that mitochondria themselves have an acute osmo-sensing mechanism. Additionally, we demonstrate that Warburg-like remodeling is required for HeLa cells to maintain ATP levels and survive under hyperosmotic conditions. Collectively, our findings suggest that cells exhibit acute metabolic remodeling under osmotic stress via the regulation of PDH phosphorylation by direct osmosensing within mitochondria.

Keywords:  Acyl-carnitine; Metabolic remodeling; Mitochondria; Osmotic stress; Pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.jbc.2022.102837
Am J Physiol Cell Physiol. 2022 Dec 26.

The impact of high fat feeding and Parkin overexpression on skeletal muscle mass, mitochondrial respiration and H2O2 emission.

Olivier Reynaud, Jennifer Wang, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Maude Dulac, Sabah N A Hussain, Raynald Bergeron, Gilles Gouspillou.

  Obesity is a major risk factor for developing various health problems, including insulin resistance and type 2 diabetes. Although controversial, accumulation of mitochondrial dysfunction, and notably an increase in mitochondrial reactive oxygen species (ROS) production, was proposed as a key contributor leading to obesity-induced insulin resistance. Here, our goal was to investigate whether Parkin overexpression, a key regulator of the removal of dysfunctional mitochondria through mitophagy, could confer protection against obesity-induced mitochondrial dysfunction. To this end, intramuscular injections of adeno-associated viruses (AAV) were performed to overexpress Parkin in limb muscle of 6-month-old mice fed a control diet (CD) or a high fat diet (HFD) for 12 weeks. An AAV expressing GFP was used as control. HFD increased fat mass, altered glycemia and resulted in insulin resistance. Parkin overexpression resulted in an increase in muscle mass in both CD and HFD mice. In CD mice, Parkin overexpression increased maximal mitochondrial respiration and lowered H2O2 emission. HFD increased mitochondrial respiration and, surprisingly, also lowered H2O2 emission. Parkin overexpression did not significantly impact mitochondrial function in HFD mice. Taken altogether, our results indicate that Parkin overexpression positively impacts muscle and mitochondrial health under basal conditions and challenge the notion that intrinsic mitochondrial dysfunction is involved in the development of insulin resistance caused by high fat feeding.

Keywords:  High fat diet; insulin resistance; mitochondrial function; obesity; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00388.2022
Free Radic Biol Med. 2022 Dec 22. pii: S0891-5849(22)01108-X. [Epub ahead of print]195 47-57

Doxorubicin induces cardiomyocyte death owing to the accumulation of dysfunctional mitochondria by inhibiting the autophagy fusion process.

Noriko Toda, Takeya Sato, Mikio Muraoka, Delan Lin, Masaki Saito, Guanje Li, Qui-Chao Song, Teruyuki Yanagisawa, Masanori Yamauchi.

  Doxorubicin (Dox), an anthracycline antibiotic, is an anticancer drug that inhibits DNA replication and cellular metabolic processes in cancer cells with high proliferative potential. However, Dox causes severe side effects, including myocardial damage and heart failure, but the molecular mechanism underlying Dox-induced myocardial injury remains uncertain. In the present study, we evaluated the effects of Dox on the mitochondrial quality control system and regulation of mitochondrial respiration and autophagy in an in vitro rat myoblast H9c2 cell culture model using western blotting, immunohistochemistry, the Seahorse XF24 system, and flow cytometry. Our results showed that Dox did not impair the initiation of autophagic flux or the functions of lysosomes; however, Dox affected the mitochondrial quality control system, leading to a fission-dominant morphology and impaired regulation of mitochondrial respiration, thereby increasing oxidative stress and inhibited progression of autophagy, particularly the fusion of autophagosomes with lysosomes. This inhibition caused a significant decrease in the formation of autolysosomes and was responsible for the accumulation of dysfunctional mitochondria and subsequent increase in oxidative stress, eventually leading to increased myocardial cell death.

Keywords:  Autophagosome; Autophagy; Doxorubicin; Mitochondria; Syntaxin 17; Vesicle-associated membrane protein 8

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.082
Biochim Biophys Acta Gen Subj. 2022 Dec 25. pii: S0304-4165(22)00220-3. [Epub ahead of print] 130302

Transgenic type2 diabetes mouse models for in vivo redox measurement of hepatic mitochondrial oxidative stress.

Naomi Kamimura, Alexander M Wolf, Takashi Yokota, Chikako Nito, Hiroshi Takahashi, Shigeo Ohta.

  BACKGROUND: Oxidative stress is involved in the progression of diabetes and its associated complications. However, it is unclear whether increased oxidative stress plays a primary role in the onset of diabetes or is a secondary indicator caused by tissue damage. Previous methods of analyzing oxidative stress have involved measuring the changes in oxidative stress biomarkers. Our aim is to identify a novel approach to clarify whether oxidative stress plays a primary role in the onset of diabetes.METHODS: We constructed transgenic type 2 diabetes mouse models expressing redox-sensitive green fluorescent proteins (roGFPs) that distinguished between mitochondria and whole cells. Pancreas, liver, skeletal muscle, and kidney redox states were measured in vivo.
RESULTS: Hepatic mitochondrial oxidation increased when the mice were 4 weeks old and continued to increase in an age-dependent manner. The increase in hepatic mitochondrial oxidation occurred simultaneously with weight gain and increased blood insulin levels before the blood glucose levels increased. Administering the oxidative stress inducer acetaminophen increased the vulnerability of the liver mitochondria to oxidative stress.
CONCLUSIONS: This study demonstrates that oxidative stress in liver mitochondria in mice begins at the onset of diabetes rather than after the disease has progressed.
GENERAL SIGNIFICANCE: RoGFP-expressing transgenic type 2 diabetes mouse models are effective and convenient tools for measuring hepatic mitochondrial redox statuses in vivo. These models may be used to assess mitochondria-targeting antioxidants and establish the role of oxidative stress in type 2 diabetes.

Keywords:  Biosensing technique; Diabetes; Disease model; Liver; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1016/j.bbagen.2022.130302
Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]

Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.

Ya-Ting Wang, Alissa J Trzeciak, Waleska Saitz Rojas, Pedro Saavedra, Yan-Ting Chen, Rachel Chirayil, Jon Iker Etchegaray, Christopher D Lucas, Daniel J Puleston, Kayvan R Keshari, Justin S A Perry.

  Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.

Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia

DOI:  https://doi.org/10.1016/j.cmet.2022.12.005