bims-mikwok 2024-01-07 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2024–01–07
twenty-six papers selected by
Gavin McStay, Liverpool John Moores University

Fission-independent compartmentalization of mitochondria during budding yeast cell division.
The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.
FUNDC1-induced mitophagy protects spinal cord neurons against ischemic injury.
Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.
Mitochondrial quality control in liver fibrosis: Epigenetic hallmarks and therapeutic strategies.
HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
Mitochondrial-derived vesicles in metabolism, disease, and aging.
SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.
The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.
Potential roles for mitochondria-to-HSF1 signaling in health and disease.
The mitochondrial protease PARL is required for spermatogenesis.
LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function.
Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.
Mitochondrial outer membrane translocase MoTom20 modulates mitochondrial morphology and is important for infectious growth of the rice blast fungus.
PINK1 restrains periodontitis-induced bone loss by preventing osteoclast mitophagy impairment.
MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.
Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.
Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways.
METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury.
Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.
Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.
Role of mitochondrial fission in stress susceptibility.
Calcium supplementation attenuates fluoride-induced bone injury via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis in mice.
IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.
Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake.
circELP2 reverse-splicing biogenesis and function as a pro-fibrogenic factor by targeting mitochondrial quality control pathway.

J Cell Biol. 2024 Mar 04. pii: e202211048. [Epub ahead of print]223(3):

Fission-independent compartmentalization of mitochondria during budding yeast cell division.

Saori R Yoshii, Yves Barral.

Lateral diffusion barriers compartmentalize membranes to generate polarity or asymmetrically partition membrane-associated macromolecules. Budding yeasts assemble such barriers in the endoplasmic reticulum (ER) and the outer nuclear envelope at the bud neck to retain aging factors in the mother cell and generate naïve and rejuvenated daughter cells. However, little is known about whether other organelles are similarly compartmentalized. Here, we show that the membranes of mitochondria are laterally compartmentalized at the bud neck and near the cell poles. The barriers in the inner mitochondrial membrane are constitutive, whereas those in the outer membrane form in response to stresses. The strength of mitochondrial diffusion barriers is regulated positively by spatial cues from the septin axis and negatively by retrograde (RTG) signaling. These data indicate that mitochondria are compartmentalized in a fission-independent manner. We propose that these diffusion barriers promote mitochondrial polarity and contribute to mitochondrial quality control.

DOI: https://doi.org/10.1083/jcb.202211048
Sci Rep. 2024 Jan 04. 14(1): 546

The nascent polypeptide-associated complex subunit Egd1 is required for efficient selective mitochondrial degradation in budding yeast.

Yuan Tian, Koji Okamoto.

Selective degradation of dysfunctional or excess mitochondria is a fundamental process crucial for cell homeostasis in almost all eukaryotes. This process relies on autophagy, an intracellular self-eating system conserved from yeast to humans and is thus called mitophagy. Detailed mechanisms of mitophagy remain to be fully understood. Here we show that mitochondrial degradation in budding yeast, which requires the pro-mitophagic protein Atg32, is strongly reduced in cells lacking Egd1, a beta subunit of the nascent polypeptide-associated complex acting in cytosolic ribosome attachment and protein targeting to mitochondria. By contrast, loss of the sole alpha subunit Egd2 or the beta subunit paralogue Btt1 led to only a partial or slight reduction in mitophagy. We also found that phosphorylation of Atg32, a crucial step for priming mitophagy, is decreased in the absence of Egd1. Forced Atg32 hyperphosphorylation almost completely restored mitophagy in egd1-null cells. Together, we propose that Egd1 acts in Atg32 phosphorylation to facilitate mitophagy.

DOI: https://doi.org/10.1038/s41598-023-50245-7
Cell Death Discov. 2024 Jan 05. 10(1): 4

FUNDC1-induced mitophagy protects spinal cord neurons against ischemic injury.

Dehui Chen, Linquan Zhou, Gang Chen, Taotao Lin, Jiemin Lin, Xin Zhao, Wenwen Li, Shengyu Guo, Rongcan Wu, Zhenyu Wang, Wenge Liu.

Local ischemia and hypoxia are the most important pathological processes in the early phase of secondary spinal cord injury (SCI), in which mitochondria are the main target of ischemic injury. Mitochondrial autophagy, also known as mitophagy, acts as a selective autophagy that specifically identifies and degrades damaged mitochondria, thereby reducing mitochondria-dependent apoptosis. Accumulating evidence shows that the mitophagy receptor, FUN14 domain-containing 1 (FUNDC1), plays an important role in ischemic injury, but the role of FUNDC1 in SCI has not been reported. In this study, we aimed to investigate whether FUNDC1 can enhance mitophagy and inhibit neuronal apoptosis in the early stage of SCI. In a rat SCI model, we found that FUNDC1 overexpression enhanced neuronal autophagy and decreased neuronal apoptosis in the early stage of injury, thereby reducing spinal cord damage. In vitro studies showed that the neuroprotective effects of FUNDC1 were achieved by inhibiting mitochondria-dependent apoptosis and improving mitochondrial function. In addition, FUNDC1 enhanced mitophagy. The protective effects of FUNDC1 against apoptosis and mitochondrial dysfunction were reversed by 3-methyladenine (3-MA), an autophagy inhibitor. Taken together, our results confirm that FUNDC1 can protect against neuronal loss after SCI by inducing mitophagy, inhibiting mitochondria-dependent apoptosis, and improving mitochondrial function.

DOI: https://doi.org/10.1038/s41420-023-01780-9
Nat Commun. 2024 Jan 02. 15(1): 52

Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif.

Isabel Pérez-Jover, Kristy Rochon, Di Hu, Mukesh Mahajan, Pooja Madan Mohan, Isaac Santos-Pérez, Julene Ormaetxea Gisasola, Juan Manuel Martinez Galvez, Jon Agirre, Xin Qi, Jason A Mears, Anna V Shnyrova, Rajesh Ramachandran.

The mechanochemical GTPase dynamin-related protein 1 (Drp1) catalyzes mitochondrial and peroxisomal fission, but the regulatory mechanisms remain ambiguous. Here we find that a conserved, intrinsically disordered, six-residue Short Linear Motif at the extreme Drp1 C-terminus, named CT-SLiM, constitutes a critical allosteric site that controls Drp1 structure and function in vitro and in vivo. Extension of the CT-SLiM by non-native residues, or its interaction with the protein partner GIPC-1, constrains Drp1 subunit conformational dynamics, alters self-assembly properties, and limits cooperative GTP hydrolysis, surprisingly leading to the fission of model membranes in vitro. In vivo, the involvement of the native CT-SLiM is critical for productive mitochondrial and peroxisomal fission, as both deletion and non-native extension of the CT-SLiM severely impair their progression. Thus, contrary to prevailing models, Drp1-catalyzed membrane fission relies on allosteric communication mediated by the CT-SLiM, deceleration of GTPase activity, and coupled changes in subunit architecture and assembly-disassembly dynamics.

DOI: https://doi.org/10.1038/s41467-023-44413-6
Cell Signal. 2024 Jan 03. pii: S0898-6568(24)00003-2. [Epub ahead of print] 111035

Mitochondrial quality control in liver fibrosis: Epigenetic hallmarks and therapeutic strategies.

Lin Jia, Yang Yang, Feng Sun, Hui Tao, Chao Lu, Jing-Jing Yang.

   BACKGROUND AND AIM: Mitochondrial quality control (MQC) plays a significant role in the progression of liver fibrosis, with key processes such as mitochondrial fission, fusion, mitophagy and biogenesis maintaining mitochondrial homeostasis. To understand the molecular mechanisms underlying epigenetic regulation of mitochondrial quality control in liver fibrosis, with the aim of uncovering novel therapeutic targets for treating, mitigating, and potentially reversing liver fibrosis, in light of the most recent advances in this field.
METHODS: We searched PubMed, Web of Science, and Scopus for published manuscripts using terms "mitochondrial quality control" "mitochondrial fission" "mitochondrial fusion" "mitochondrial biogenesis" "mitophagy" "liver fibrosis" "epigenetic regulation" "DNA methylation" "RNA methylation" "histone modification" and "non-coding RNA". Manuscripts were collated, studied and carried forward for discussion where appropriate.
RESULTS: Mitochondrial fission, fusion, biogenesis, and mitophagy regulate the homeostasis of mitochondria, and the imbalance of mitochondrial homeostasis can induce liver fibrosis. Epigenetic regulation, including DNA methylation, RNA methylation, histone modifications, and non-coding RNAs, plays a significant role in regulating the processes of mitochondrial homeostasis.
CONCLUSION: Mitochondrial quality control and epigenetic mechanisms are intricately linked to the pathogenesis of liver fibrosis. Understanding these molecular interactions provides insight into potential therapeutic strategies. Further research is necessary to translate these findings into clinical applications, with a focus on developing epigenetic drugs to ameliorate liver fibrosis by modulating MQC and epigenetic pathways.

Keywords:  Epigenetics; Liver fibrosis; Mitochondrial quality control; Molecular mechanisms

DOI:  https://doi.org/10.1016/j.cellsig.2024.111035
Proc Natl Acad Sci U S A. 2024 Jan 09. 121(2): e2306454120

HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.

Mengying Cui, Koji Yamano, Kenichi Yamamoto, Hitomi Yamamoto-Imoto, Satoshi Minami, Takeshi Yamamoto, Sho Matsui, Tatsuya Kaminishi, Takayuki Shima, Monami Ogura, Megumi Tsuchiya, Kohei Nishino, Brian T Layden, Hisakazu Kato, Hidesato Ogawa, Shinya Oki, Yukinori Okada, Yoshitaka Isaka, Hidetaka Kosako, Noriyuki Matsuda, Tamotsu Yoshimori, Shuhei Nakamura.

  Mitochondrial and lysosomal functions are intimately linked and are critical for cellular homeostasis, as evidenced by the fact that cellular senescence, aging, and multiple prominent diseases are associated with concomitant dysfunction of both organelles. However, it is not well understood how the two important organelles are regulated. Transcription factor EB (TFEB) is the master regulator of lysosomal function and is also implicated in regulating mitochondrial function; however, the mechanism underlying the maintenance of both organelles remains to be fully elucidated. Here, by comprehensive transcriptome analysis and subsequent chromatin immunoprecipitation-qPCR, we identified hexokinase domain containing 1 (HKDC1), which is known to function in the glycolysis pathway as a direct TFEB target. Moreover, HKDC1 was upregulated in both mitochondrial and lysosomal stress in a TFEB-dependent manner, and its function was critical for the maintenance of both organelles under stress conditions. Mechanistically, the TFEB-HKDC1 axis was essential for PINK1 (PTEN-induced kinase 1)/Parkin-dependent mitophagy via its initial step, PINK1 stabilization. In addition, the functions of HKDC1 and voltage-dependent anion channels, with which HKDC1 interacts, were essential for the clearance of damaged lysosomes and maintaining mitochondria-lysosome contact. Interestingly, HKDC1 regulated mitophagy and lysosomal repair independently of its prospective function in glycolysis. Furthermore, loss function of HKDC1 accelerated DNA damage-induced cellular senescence with the accumulation of hyperfused mitochondria and damaged lysosomes. Our results show that HKDC1, a factor downstream of TFEB, maintains both mitochondrial and lysosomal homeostasis, which is critical to prevent cellular senescence.

Keywords:  HKDC1; TFEB; cellular senescence; mitochondria–lysosome contact; mitophagy

DOI:  https://doi.org/10.1073/pnas.2306454120
Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00446-1. [Epub ahead of print]36(1): 21-35

Mitochondrial-derived vesicles in metabolism, disease, and aging.

Tim König, Heidi M McBride.

Mitochondria are central hubs of cellular metabolism and are tightly connected to signaling pathways. The dynamic plasticity of mitochondria to fuse, divide, and contact other organelles to flux metabolites is central to their function. To ensure bona fide functionality and signaling interconnectivity, diverse molecular mechanisms evolved. An ancient and long-overlooked mechanism is the generation of mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes to target organelles. Just recently, we gained significant insight into the mechanisms and functions of MDV transport, ranging from their role in mitochondrial quality control to immune signaling, thus demonstrating unexpected and diverse physiological aspects of MDV transport. This review highlights the origin of MDVs, their biogenesis, and their cargo selection, with a specific focus on the contribution of MDV transport to signaling across cell and organ barriers. Additionally, the implications of MDVs in peroxisome biogenesis, neurodegeneration, metabolism, aging, and cancer are discussed.

DOI: https://doi.org/10.1016/j.cmet.2023.11.014
Free Radic Biol Med. 2023 Dec 27. pii: S0891-5849(23)01184-X. [Epub ahead of print]212 220-233

SYNJ2BP ameliorates intervertebral disc degeneration by facilitating mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial Zn2+ homeostasis.

Yu Song, Wen Geng, Dingchao Zhu, Huaizhen Liang, Zhi Du, Bide Tong, Kun Wang, Shuai Li, Yong Gao, Xiaobo Feng, Zhiwei Liao, Rongcheng Mei, Cao Yang.

  Nucleus pulposus (NP) cell function-loss is one main contributor during intervertebral disc degeneration (IDD) progression. Both mitochondria and endoplasmic reticulum (ER) play vital roles in sustaining NP cell homeostasis, while the precise function of ER-mitochondria tethering and cross talk in IDD remain to be clarified. Here, we demonstrated that a notable disruption of mitochondria-associated ER membrane (MAM) was identified in degenerated discs and TBHP-induced NP cells, accompanied by mitochondrial Zn2+ overload and NP cell senescence. Importantly, experimental coupling of MAM contacts by MFN2, a critical regulator of MAM formation, could enhance NLRX1-SLC39A7 complex formation and mitochondrial Zn2+ homeostasis. Further using the sequencing data from TBHP-induced degenerative model of NP cells, combining the reported MAM proteomes, we demonstrated that SYNJ2BP loss was one critical pathological characteristic of NP cell senescence and IDD progression, which showed close relationship with MAM disruption. Overexpression of SYNJ2BP could facilitate MAM contact organization and NLRX1-SLC39A7 complex formation, thus promoted mitochondrial Zn2+ homeostasis, NP cell proliferation and intervertebral disc rejuvenation. Collectively, our present study revealed a critical role of SYNJ2BP in maintaining mitochondrial Zn2+ homeostasis in NP cells during IDD progression, partially via sustaining MAM contact and NLRX1-SLC39A7 complex formation.

Keywords:  Intervertebral disc degeneration; Mitochondria-associated ER membrane; NLRX1; Nucleus pulposus; SLC39A7; SYNJ2BP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.028
EMBO J. 2024 Jan;43(1): 32-60

The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.

Jose M Delgado, Logan Wallace Shepard, Sarah W Lamson, Samantha L Liu, Christopher J Shoemaker.

  Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. This screen revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system and the ubiquitin-proteosome system regulated BNIP3 independently. Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. More broadly, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that tightly regulate endogenous tail-anchored protein localization.

Keywords:  BNIP3; EMC; Mitophagy; Secretory Pathway; TA Protein

DOI:  https://doi.org/10.1038/s44318-023-00006-z
Front Mol Biosci. 2023 ;10 1332658

Potential roles for mitochondria-to-HSF1 signaling in health and disease.

Johnathan Labbadia.

  The ability to respond rapidly and efficiently to protein misfolding is crucial for development, reproduction and long-term health. Cells respond to imbalances in cytosolic/nuclear protein homeostasis through the Heat Shock Response, a tightly regulated transcriptional program that enhances protein homeostasis capacity by increasing levels of protein quality control factors. The Heat Shock Response is driven by Heat Shock Factor 1, which is rapidly activated by the appearance of misfolded proteins and drives the expression of genes encoding molecular chaperones and protein degradation factors, thereby restoring proteome integrity. HSF1 is critical for organismal health, and this has largely been attributed to the preservation of cytosolic and nuclear protein homeostasis. However, evidence is now emerging that HSF1 is also a key mediator of mitochondrial function, raising the possibility that many of the health benefits conferred by HSF1 may be due to the maintenance of mitochondrial homeostasis. In this review, I will discuss our current understanding of the interplay between HSF1 and mitochondria and consider how mitochondria-to-HSF1 signaling may influence health and disease susceptibility.

Keywords:  HSF1; ageing; development; disease; mitochondria; protein homeostasis

DOI:  https://doi.org/10.3389/fmolb.2023.1332658
Commun Biol. 2024 Jan 05. 7(1): 44

The mitochondrial protease PARL is required for spermatogenesis.

Sarah Schumacher, Laura Klose, Jessica Lambertz, Dieter Lütjohann, Ronald Biemann, Stefanie Kuerten, Lars Fester.

Mitochondrial function plays an important role in the maintenance of male fertility. However, the mechanisms underlying mitochondrial defect-related infertility remain mostly unclear. Here we show that a deficiency of PARL (Parl-/-), a mitochondrial protease, causes complete arrest of spermatogenesis during meiosis I. PARL deficiency led to severe downregulation of proteins of respiratory chain complex IV in testes that did not occur in other tested organs, causing a deficit in complex IV activity and ATP production. Furthermore, Parl-/- testes showed an almost complete loss of HSD17B3, a protein of the sER responsible for the last step in testosterone synthesis. While testosterone production appeared to be restored by overexpression of HSD17B12, loss of the canonical testosterone synthesis led to an upregulation of luteinizing hormone (LH) and of LH-regulated responses. These results suggest an important impact of the downstream regulation of mitochondrial defects that manifest in a cell-type-specific manner and extend beyond mitochondria.

DOI: https://doi.org/10.1038/s42003-023-05703-3
RNA. 2023 Dec 20. pii: rna.079799.123. [Epub ahead of print]

LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function.

Benjamin M Lewis, Chae Yun Cho, Hsuan-Lin Her, Orel Mizrahi, Tony Hunter, Gene W Yeo.

  Mitochondria-associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples known, we set out to identify RBPs that regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our systematic analysis of RNA targets of 150 RBPs identified RBPs with a preference for binding NEMmRNAs, including LARP4, a La RBP family member. We show that LARP4's targets are particularly enriched in mRNAs that encode respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. Through quantitative proteomics, we demonstrate that depletion of LARP4 leads to a significant reduction in RCCP and MRP protein levels. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that LARP4 re-expression rescues this phenotype. Our findings shed light on a novel function for LARP4 as an RBP that binds to and positively regulates NEMmRNAs to promote mitochondrial respiratory function.

Keywords:  La module protein; Mitochondria; RNA binding protein; Translation; eCLIP

DOI:  https://doi.org/10.1261/rna.079799.123
Annu Rev Biophys. 2024 Jan 02.

Mitochondrial Dynamics at Different Levels: From Cristae Dynamics to Interorganellar Cross Talk.

Arun Kumar Kondadi, Andreas S Reichert.

Mitochondria are essential organelles performing important cellular functions ranging from bioenergetics and metabolism to apoptotic signaling and immune responses. They are highly dynamic at different structural and functional levels. Mitochondria have been shown to constantly undergo fusion and fission processes and dynamically interact with other organelles such as the endoplasmic reticulum, peroxisomes, and lipid droplets. The field of mitochondrial dynamics has evolved hand in hand with technological achievements including advanced fluorescence super-resolution nanoscopy. Dynamic remodeling of the cristae membrane within individual mitochondria, discovered very recently, opens up a further exciting layer of mitochondrial dynamics. In this review, we discuss mitochondrial dynamics at the following levels: (a) within an individual mitochondrion, (b) among mitochondria, and (c) between mitochondria and other organelles. Although the three tiers of mitochondrial dynamics have in the past been classified in a hierarchical manner, they are functionally connected and must act in a coordinated manner to maintain cellular functions and thus prevent various human diseases. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-biophys-030822-020736
Mol Plant Microbe Interact. 2024 Jan 03.

Mitochondrial outer membrane translocase MoTom20 modulates mitochondrial morphology and is important for infectious growth of the rice blast fungus.

Shuang Wu, Ying Zhang, Lele Xu, Haibo Zhang, Yuhe Li, Leiyun Yang, Zhengguang Zhang, Haifeng Zhang.

Mitochondria are highly dynamic organelles that constantly change their morphology to adapt the cellular environment through fission and fusion, which is critical for a cell to maintain normal cellular functions. Despite the significance of this process in the development and pathogenicity of the rice blast fungus Magnaporthe oryzae (M. oryzae), the underlying mechanism remains largely elusive. Here, we identified and characterized a mitochondrial outer membrane translocase MoTom20 in M. oryzae. Targeted gene deletion revealed that MoTom20 plays an important role in vegetative growth, conidiogenesis, penetration and infectious growth of M. oryzae. The growth rate, conidial production, appressorium turgor and pathogenicity are decreased in the ΔMotom20 mutant compared to that in the wild type and complemented strains. Further analysis revealed that MoTom20 localizes in mitochondrion and plays a key role in regulating mitochondrial fission and fusion balance which is critical for infectious growth. Finally, we found that MoTom20 is involved in fatty acid utilization and its yeast homolog ScTom20 is able to rescue the defects of ΔMotom20 in mitochondrial morphology and pathogenicity. Overall, our data demonstrate that MoTom20 is a key regulator for mitochondrial morphology maintenance which is important for infectious growth of the rice blast fungus.

DOI: https://doi.org/10.1094/MPMI-10-23-0168-R
Redox Biol. 2023 Dec 30. pii: S2213-2317(23)00424-X. [Epub ahead of print]69 103023

PINK1 restrains periodontitis-induced bone loss by preventing osteoclast mitophagy impairment.

Ji Sun Jang, Seo Jin Hong, Shenzheng Mo, Min Kyung Kim, Yong-Gun Kim, Youngkyun Lee, Hong-Hee Kim.

  The oral colonization of periodontal pathogens onto gingival tissues establishes hypoxic microenvironment, often disrupting periodontal homeostasis in conjunction with oxidative stress. The association between reactive oxygen species (ROS) and osteolytic periodontitis have been suggested by recent studies. PTEN-induced kinase 1 (PINK1), a mitochondrial serine/threonine kinase, is an essential protein for mitochondrial quality control as it protects cells from oxidative stress by promoting degradation of damaged mitochondria through mitophagy. However, the pathophysiological roles of PINK1 in osteoclast-mediated bone loss have not been explored. Here we aimed to determine whether PINK1 plays a role in the regulation of osteoclastogenesis and alveolar bone resorption associated with periodontitis. C57BL/6 wild type (WT) and Pink1 knockout (KO) mice were subjected to ligature-induced periodontitis (LIP), and alveolar bones were evaluated by μCT-analysis and tartrate-resistant acid phosphatase (TRAP) staining. The μCT-analysis showed that bone volume fraction and travecular thickness were lower in Pink1 KO compared to WT mice. The number of TRAP-positive osteoclasts was markedly increased in the periodontal tissues of Pink1 KO mice with LIP. The genetic silencing or deletion of Pink1 promoted excessive osteoclast differentiation and bone resorption in vitro, as respectively indicated by TRAP staining and resorption pits on dentin slices. PINK1 deficiency led to mitochondrial instabilities as indicated by confocal microscopy of mitochondrial ROS, mitochondrial oxygen consumption rate (OCR) analysis, and transmission electron microscopy (TEM). Consequently, a significant increase in Ca2+-nuclear factor of activated T cells 1 (NFATc1) signaling was also found. On the other hand, restoration of mitophagy and autophagy by spermidine (SPD) treatment and the resolution of oxidative stress by N-acetyl-l-cysteine (NAC) treatment protected PINK1 deficiency-induced excessive generation of osteoclasts. Taken together, our findings demonstrate that PINK1 is essential for maintaining mitochondrial homeostasis during osteoclast differentiation. Therefore, targeting PINK1 may provide a novel therapeutic strategy for severe periodontitis with fulminant osteolysis.

Keywords:  Mitophagy; Osteoclast; PINK1; Periodontitis; ROS

DOI:  https://doi.org/10.1016/j.redox.2023.103023
EMBO Rep. 2023 Dec 14.

MTCH2 cooperates with MFN2 and lysophosphatidic acid synthesis to sustain mitochondrial fusion.

Andres Goldman, Michael Mullokandov, Yehudit Zaltsman, Limor Regev, Smadar Levin-Zaidman, Atan Gross.

  Fusion of the outer mitochondrial membrane (OMM) is regulated by mitofusin 1 (MFN1) and 2 (MFN2), yet the differential contribution of each of these proteins is less understood. Mitochondrial carrier homolog 2 (MTCH2) also plays a role in mitochondrial fusion, but its exact function remains unresolved. MTCH2 overexpression enforces MFN2-independent mitochondrial fusion, proposedly by modulating the phospholipid lysophosphatidic acid (LPA), which is synthesized by glycerol-phosphate acyl transferases (GPATs) in the endoplasmic reticulum (ER) and the OMM. Here we report that MTCH2 requires MFN1 to enforce mitochondrial fusion and that fragmentation caused by loss of MTCH2 can be specifically counterbalanced by overexpression of MFN2 but not MFN1, partially independent of its GTPase activity and mitochondrial localization. Pharmacological inhibition of GPATs (GPATi) or silencing ER-resident GPATs suppresses MFN2's ability to compensate for the loss of MTCH2. Loss of either MTCH2, MFN2, or GPATi does not impair stress-induced mitochondrial fusion, whereas the combined loss of MTCH2 and GPATi or the combined loss of MTCH2 and MFN2 does. Taken together, we unmask two cooperative mechanisms that sustain mitochondrial fusion.

Keywords:  LPA; MFN2; MTCH2; Mitochondria-ER Communication; Mitochondrial Fusion

DOI:  https://doi.org/10.1038/s44319-023-00009-1
J Biochem. 2023 Dec 29. pii: mvad117. [Epub ahead of print]

Mitochondrial lipid dynamics regulated by MITOL-mediated ubiquitination.

Koji Yamano, Hiroki Kinefuchi, Waka Kojima.

  Mitochondria-endoplasmic reticulum (ER) contact sites in mammals provide platforms for various reactions such as calcium signaling, lipid metabolism, organelle dynamics and autophagy. To fulfill these tasks, a number of proteins assemble at the contact sites including MITOL/MARCHF5, a critical mitochondrial ubiquitin ligase. How MITOL regulates mitochondrial function from the contact site, however, has been largely unresolved. Recently, a new role for MITOL in the active transport of phosphatidic acid from the ER to mitochondria was reported. In this commentary, we briefly summarize our current understanding of mitochondria-ER contact sites and discuss the recently elucidated mechanism of MITOL fine-tuning phospholipid transfer activity through ubiquitination.

Keywords:  contact site; mitochondria; phospholipid; ubiquitin; ubiquitin ligase

DOI:  https://doi.org/10.1093/jb/mvad117
Chem Biol Interact. 2024 Jan 03. pii: S0009-2797(24)00001-2. [Epub ahead of print] 110855

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathways.

Juncheng Si, Lili Sun, Ying Qin, Lina Peng, Yongshan Gong, Chun Gao, Wenhui Shen, Mengqi Li.

  Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the effects of CBD on the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of Pink1, Parkin and Bnip3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the Pink1/Parkin and Bnip3 pathway.

Keywords:  Cannabinoid; Exhaustive exercise; Mitophagy; Skeletal muscle; Transcriptome

DOI:  https://doi.org/10.1016/j.cbi.2024.110855
Int J Biol Sci. 2024 ;20(2): 433-445

METTL3 boosts mitochondrial fission and induces cardiac fibrosis after ischemia/reperfusion injury.

Li Ma, Xing Chang, Jing Gao, Ying Zhang, Ye Chen, Hao Zhou, Na Zhou, Na Du, Jiamin Li, Jiachen Bi, Ziyue Chen, Xinxin Chen, Qingyong He.

  METTL3, an RNA methyltransferase enzyme, exerts therapeutic effects on various cardiovascular diseases. Myocardial ischemia-reperfusion injury (MIRI) and subsequently cardiac fibrosis is linked to acute cardiomyocyte death or dysfunction induced by mitochondrial damage, particularly mitochondrial fission. Our research aims to elucidate the potential mechanisms underlying the therapeutic actions of METTL3 in MIRI, with focus on mitochondrial fission. When compared with Mettl3flox mice subjected to MIRI, Mettl3 cardiomyocyte knockout (Mettl3Cko) mice have reduced infarct size, decreased serum levels of myocardial injury-related factors, limited cardiac fibrosis, and preserved myocardial ultrastructure and contractile/relaxation capacity. The cardioprotective actions of Mettl3 knockout were associated with reduced inflammatory responses, decreased myocardial neutrophil infiltration, and suppression of cardiomyocyte death. Through signaling pathway validation experiments and assays in cultured HL-1 cardiomyocytes exposed to hypoxia/reoxygenation, we confirmed that Mettl3 deficiency interfere with DNA-PKcs phosphorylation, thereby blocking the downstream activation of Fis1 and preventing pathological mitochondrial fission. In conclusion, this study confirms that inhibition of METTL3 can alleviate myocardial cardiac fibrosis inflammation and prevent cardiomyocyte death under reperfusion injury conditions by disrupting DNA-PKcs/Fis1-dependent mitochondrial fission, ultimately improving cardiac function. These findings suggest new approaches for clinical intervention in patients with MIRI.

Keywords:  DNA-PKcs; Fis1; METTL3; cardiac ischemia-reperfusion injury.; mitochondrial fission

DOI:  https://doi.org/10.7150/ijbs.87535
Curr Biol. 2023 Dec 28. pii: S0960-9822(23)01660-3. [Epub ahead of print]

Mitochondria-derived reactive oxygen species are the likely primary trigger of mitochondrial retrograde signaling in Arabidopsis.

Kasim Khan, Huy Cuong Tran, Berivan Mansuroglu, Pinar Önsell, Stefano Buratti, Markus Schwarzländer, Alex Costa, Allan G Rasmusson, Olivier Van Aken.

  Besides their central function in respiration, plant mitochondria play a crucial role in maintaining cellular homeostasis during stress by providing "retrograde" feedback to the nucleus. Despite the growing understanding of this signaling network, the nature of the signals that initiate mitochondrial retrograde regulation (MRR) in plants remains unknown. Here, we investigated the dynamics and causative relationship of a wide range of mitochondria-related parameters for MRR, using a combination of Arabidopsis fluorescent protein biosensor lines, in vitro assays, and genetic and pharmacological approaches. We show that previously linked physiological parameters, including changes in cytosolic ATP, NADH/NAD+ ratio, cytosolic reactive oxygen species (ROS), pH, free Ca2+, and mitochondrial membrane potential, may often be correlated with-but are not the primary drivers of-MRR induction in plants. However, we demonstrate that the induced production of mitochondrial ROS is the likely primary trigger for MRR induction in Arabidopsis. Furthermore, we demonstrate that mitochondrial ROS-mediated signaling uses the ER-localized ANAC017-pathway to induce MRR response. Finally, our data suggest that mitochondrially generated ROS can induce MRR without substantially leaking into other cellular compartments such as the cytosol or ER lumen, as previously proposed. Overall, our results offer compelling evidence that mitochondrial ROS elevation is the likely trigger of MRR.

Keywords:  Arabidopsis; mitochondria; reactive oxygen species; retrograde signaling

DOI:  https://doi.org/10.1016/j.cub.2023.12.005
Mol Cell Biochem. 2023 Dec 29.

Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.

Da Huo, Xin-Yu Bi, Jun-Ling Zeng, Da-Mao Dai, Xiang-Lin Dong.

  Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-β)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-β/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-β/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-β/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-β pathway, Notch pathway, and TGF-β/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-β/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-β/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-β/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.

Keywords:  DAPT; Hypertrophic scar formation; Mitochondrial fusion; Pirfenidone; SIS3; TGF-β/Notch interaction

DOI:  https://doi.org/10.1007/s11010-023-04912-y
Lab Anim (NY). 2024 Jan;53(1): 8

Role of mitochondrial fission in stress susceptibility.

Jorge Ferreira.

DOI: https://doi.org/10.1038/s41684-023-01311-0
J Hazard Mater. 2024 Jan 02. pii: S0304-3894(23)02695-X. [Epub ahead of print]465 133411

Calcium supplementation attenuates fluoride-induced bone injury via PINK1/Parkin-mediated mitophagy and mitochondrial apoptosis in mice.

Yingjun Hu, Yuanyuan Li, Meng Li, Tianrui Zhao, Wenhui Zhang, Yinghui Wang, Yang He, Hui Zhao, Haojie Li, Tianyu Wang, Yangfei Zhao, Jundong Wang, Jinming Wang.

  Excessive consumption of fluoride can cause skeletal fluorosis. Mitophagy has been identified as a novel target for bone disorders. Meanwhile, calcium supplementation has shown great potential for mitigating fluoride-related bone damage. Hence, this study aimed to elucidate the association between mitophagy and skeletal fluorosis and the precise mechanisms through which calcium alleviates these injuries. A 100 mg/L sodium fluoride (NaF) exposure model in Parkin knockout (Parkin-/-) mice and a 100 mg/L NaF exposure mouse model with 1% calcium carbonate (CaCO3) intervention were established in the current study. Fluoride exposure caused the impairment of mitochondria and activation of PTEN-induced putative kinase1 (PINK1)/E3 ubiquitin ligase Park2 (Parkin)-mediated mitophagy and mitochondrial apoptosis in the bones, which were restored after blocking Parkin. Additionally, the intervention model showed fluoride-exposed mice exhibited abnormal bone trabecula and mechanical properties. Still, these bone injuries could be effectively attenuated by adding 1% calcium to their diet, which reversed fluoride-activated mitophagy and apoptosis. To summarize, fluoride can activate bone mitophagy through the PINK1/Parkin pathway and mitochondrial apoptosis. Parkin-/- and 1% calcium provide protection against fluoride-induced bone damage. Notably, this study provides theoretical bases for the prevention and therapy of animal and human health and safety caused by environmental fluoride contamination.

Keywords:  Calcium therapy; Mitophagy; PINK1/Parkin pathway; Skeletal fluorosis; Trace element

DOI:  https://doi.org/10.1016/j.jhazmat.2023.133411
Cardiovasc Res. 2024 Jan 02. pii: cvad145. [Epub ahead of print]

IKKβ stabilizes Mitofusin 2 and suppresses doxorubicin cardiomyopathy.

Matthew Guberman, Rimpy Dhingra, Jenna Cross, Victoria Margulets, Hongying Gang, Inna Rabinovich-Nikitin, Lorrie A Kirshenbaum.

   AIMS: The mitochondrial dynamics protein Mitofusin 2 (MFN2) coordinates critical cellular processes including mitochondrial bioenergetics, quality control, and cell viability. The NF-κB kinase IKKβ suppresses mitochondrial injury in doxorubicin cardiomyopathy, but the underlying mechanism is undefined.
METHODS AND RESULTS: Herein, we identify a novel signalling axis that functionally connects IKKβ and doxorubicin cardiomyopathy to a mechanism that impinges upon the proteasomal stabilization of MFN2. In contrast to vehicle-treated cells, MFN2 was highly ubiquitinated and rapidly degraded by the proteasomal-regulated pathway in cardiac myocytes treated with doxorubicin. The loss of MFN2 activity resulted in mitochondrial perturbations, including increased reactive oxygen species (ROS) production, impaired respiration, and necrotic cell death. Interestingly, doxorubicin-induced degradation of MFN2 and mitochondrial-regulated cell death were contingent upon IKKβ kinase activity. Notably, immunoprecipitation and proximity ligation assays revealed that IKKβ interacted with MFN2 suggesting that MFN2 may be a phosphorylation target of IKKβ. To explore this possibility, mass spectrometry analysis identified a novel MFN2 phospho-acceptor site at serine 53 that was phosphorylated by wild-type IKKβ but not by a kinase-inactive mutant IKKβK-M. Based on these findings, we reasoned that IKKβ-mediated phosphorylation of serine 53 may influence MFN2 protein stability. Consistent with this view, an IKKβ-phosphomimetic MFN2 (MFN2S53D) was resistant to proteasomal degradation induced by doxorubicin whereas wild-type MFN2 and IKKβ-phosphorylation defective MFN2 mutant (MFNS53A) were readily degraded in cardiac myocytes treated with doxorubicin. Concordantly, gain of function of IKKβ or MFN2S53D suppressed doxorubicin-induced mitochondrial injury and cell death.
CONCLUSIONS: The findings of this study reveal a novel survival pathway for IKKβ that is mutually dependent upon and obligatory linked to the phosphorylation and stabilization of the mitochondrial dynamics protein MFN2.

Keywords:  Cardiac myocytes; Cell death; Doxorubicin; IKKβ; MFN2; Mitochondria

DOI:  https://doi.org/10.1093/cvr/cvad145
Nutr Metab (Lond). 2024 Jan 02. 21(1): 4

Dysregulation of mitochondrial dynamics mediated aortic perivascular adipose tissue-associated vascular reactivity impairment under excessive fructose intake.

Kay L H Wu, Chih-Wei Wu, Lee-Wei Chen, Hsiao-Huang Chang, Ching-Li Cheng, Cai-Yi Wu, Yu-Chi Lee, I-Chun Chen, Chun-Ying Hung, Wen-Chung Liu.

  Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

Keywords:  Adipose whitening; High fructose diet; Mitochondrial dynamics; Perivascular adipose tissue; Vascular reactivity

DOI:  https://doi.org/10.1186/s12986-023-00776-7
J Cell Mol Med. 2023 Dec 30.

circELP2 reverse-splicing biogenesis and function as a pro-fibrogenic factor by targeting mitochondrial quality control pathway.

Songzi Zhang, Diwei Tu, Weili Liu, Ruiqiong Li, Mengqi Jiang, Xinglong Yuan, Jianlin Luan, Hongbo Li, Changjun Lv, Xiaodong Song.

  Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.

Keywords:  YAP1/TAZ; circRNA; miRNA; mitochondrial quality control pathway; pulmonary fibrosis

DOI:  https://doi.org/10.1111/jcmm.18098