bims-mitdyn 2023-05-28 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2023–05–28
eleven papers selected by
Edmond Chan, Queen’s University, School of Medicine

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.
Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis.
Oxidization of optic atrophy 1 cysteines occurs during heart ischemia-reperfusion and amplifies cell death by oxidative stress.
Enhanced mitochondrial fission inhibits triple-negative breast cancer cell migration through an ROS-dependent mechanism.
Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death.
A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.
Host cell egress of Brucella abortus requires BNIP3L-mediated mitophagy.
Coronaviral ORF6 protein mediates inter-organelle contacts and modulates host cell lipid flux for virus production.
Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.
Mitochondrial dynamics and cristae shape changes during metabolic reprogramming.

Nat Cell Biol. 2023 May 22.

Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes.

Tingting Fu, Wanping Sun, Jiachen Xue, Zheng Zhou, Wen Wang, Qiqi Guo, Xinyi Chen, Danxia Zhou, Zhisheng Xu, Lin Liu, Liwei Xiao, Yan Mao, Likun Yang, Yujing Yin, Xue-Na Zhang, Qiangyou Wan, Bin Lu, Yuncong Chen, Min-Sheng Zhu, Philipp E Scherer, Lei Fang, Hai-Long Piao, Mengle Shao, Zhenji Gan.

Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or β3 adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.

DOI: https://doi.org/10.1038/s41556-023-01155-3
Sci Adv. 2023 May 24. 9(21): eadg8156

Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis.

Giovanni Quarato, Luigi Mari, Nicholas J Barrows, Mao Yang, Sebastian Ruehl, Mark J Chen, Cliff S Guy, Jonathan Low, Taosheng Chen, Douglas R Green.

Degradation of defective mitochondria is an essential process to maintain cellular homeostasis and it is strictly regulated by the ubiquitin-proteasome system (UPS) and lysosomal activities. Here, using genome-wide CRISPR and small interference RNA screens, we identified a critical contribution of the lysosomal system in controlling aberrant induction of apoptosis following mitochondrial damage. After treatment with mitochondrial toxins, activation of the PINK1-Parkin axis triggered a BAX- and BAK-independent process of cytochrome c release from mitochondria followed by APAF1 and caspase 9-dependent apoptosis. This phenomenon was mediated by UPS-dependent outer mitochondrial membrane (OMM) degradation and was reversed using proteasome inhibitors. We found that the subsequent recruitment of the autophagy machinery to the OMM protected cells from apoptosis, mediating the lysosomal degradation of dysfunctional mitochondria. Our results underscore a major role of the autophagy machinery in counteracting aberrant noncanonical apoptosis and identified autophagy receptors as key elements in the regulation of this process.

DOI: https://doi.org/10.1126/sciadv.adg8156
Redox Biol. 2023 May 19. pii: S2213-2317(23)00156-8. [Epub ahead of print]63 102755

Oxidization of optic atrophy 1 cysteines occurs during heart ischemia-reperfusion and amplifies cell death by oxidative stress.

Martina Semenzato, Mark J Kohr, Charlotte Quirin, Roberta Menabò, Petra Alanova, Lukas Alan, Anna Pellattiero, Elizabeth Murphy, Fabio Di Lisa, Luca Scorrano.

During cardiac ischemia-reperfusion, excess reactive oxygen species can damage mitochondrial, cellular and organ function. Here we show that cysteine oxidation of the mitochondrial protein Opa1 contributes to mitochondrial damage and cell death caused by oxidative stress. Oxy-proteomics of ischemic-reperfused hearts reveal oxidation of the C-terminal C786 of Opa1 and treatment of perfused mouse hearts, adult cardiomyocytes, and fibroblasts with H2O2 leads to the formation of a reduction-sensitive ∼180 KDa Opa1 complex, distinct from the ∼270 KDa one antagonizing cristae remodeling. This Opa1 oxidation process is curtailed by mutation of C786 and of the other 3 Cys residues of its C-terminal domain (Opa1TetraCys). When reintroduced in Opa1-/- cells, Opa1TetraCys is not efficiently processed into short Opa1TetraCys and hence fails to fuse mitochondria. Unexpectedly, Opa1TetraCys restores mitochondrial ultrastructure in Opa1-/- cells and protects them from H2O2-induced mitochondrial depolarization, cristae remodeling, cytochrome c release and cell death. Thus, preventing the Opa1 oxidation occurring during cardiac ischemia-reperfusion reduces mitochondrial damage and cell death induced by oxidative stress independent of mitochondrial fusion.

DOI: https://doi.org/10.1016/j.redox.2023.102755
iScience. 2023 Jun 16. 26(6): 106788

Enhanced mitochondrial fission inhibits triple-negative breast cancer cell migration through an ROS-dependent mechanism.

Brock A Humphries, Anne Zhang, Johanna M Buschhaus, Avinash Bevoor, Alex Farfel, Shrila Rajendran, Alyssa C Cutter, Gary D Luker.

  Mitochondria produce reactive oxygen species (ROS), which function in signal transduction. Mitochondrial dynamics, encompassing morphological shifts between fission and fusion, can directly impact ROS levels in cancer cells. In this study, we identified an ROS-dependent mechanism for how enhanced mitochondrial fission inhibits triple negative breast cancer (TNBC) cell migration. We found that enforcing mitochondrial fission in TNBC resulted in an increase in intracellular ROS levels and reduced cell migration and the formation of actin-rich migratory structures. Consistent with mitochondrial fission, increasing ROS levels in cells inhibited cell migration. Conversely, reducing ROS levels with either a global or mitochondrially targeted scavenger overcame the inhibitory effects of mitochondrial fission. Mechanistically, we found that the ROS sensitive SHP-1/2 phosphatases partially regulate inhibitory effects of mitochondrial fission on TNBC migration. Overall, our work reveals the inhibitory effects of ROS in TNBC and supports mitochondrial dynamics as a potential therapeutic target for cancer.

Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2023.106788
J Cell Sci. 2023 May 26. pii: jcs.260819. [Epub ahead of print]

Optogenetically engineered Ca2+ oscillation-mediated DRP1 activation promotes mitochondrial fission and cell death.

Yi-Shyun Lai, Cheng-Chi Chang, Yong-Yi Chen, Thi My Hang Nguyen, Jixuan Xu, Ying-Chi Chen, Yu-Fen Chang, Chia-Yih Wang, Pai-Sheng Chen, Shih-Chieh Lin, I-Chen Peng, Shaw-Jenq Tsai, Wen-Tai Chiu.

  Mitochondrial dynamics regulate the quality and morphology of mitochondria. Calcium (Ca2+) plays an important role in regulating mitochondrial function. Here, we investigated the effects of optogenetically engineered Ca2+ signaling on mitochondrial dynamics. More specifically, customized illumination conditions could trigger unique Ca2+ oscillation waves to trigger specific signaling pathways. In this study, we found that modulating Ca2+ oscillations by increasing the light frequency, intensity, and exposure time could drive mitochondria toward the fission state, mitochondrial dysfunction, autophagy, and cell death. Moreover, illumination triggered phosphorylation at the Ser616 residue, but not the Ser637 residue of the mitochondrial fission protein, dynamin-related protein 1 (DRP1), via the activation of Ca2+-dependent kinases, CaMKII, ERK, and CDK1. However, optogenetically engineered Ca2+ signaling did not activate calcineurin phosphatase to dephosphorylate DRP1 at Ser637. In addition, light illumination had no effect on the expression levels of the mitochondrial fusion proteins, mitofusin (MFN)-1 and MFN2.Taken together, this study provides an effective and innovative approach to altering Ca2+ signaling for controlling mitochondrial fission with a more precise resolution than pharmacological approaches in the temporal dimension.

Keywords:  Calcium oscillation; DRP1; Mitochondrial fission; Optogenetics

DOI:  https://doi.org/10.1242/jcs.260819
EMBO Mol Med. 2023 May 24. e16951

A coordinated multiorgan metabolic response contributes to human mitochondrial myopathy.

Nneka Southwell, Guido Primiano, Viraj Nadkarni, Nabeel Attarwala, Emelie Beattie, Dawson Miller, Sumaitaah Alam, Irene Liparulo, Yevgeniya I Shurubor, Maria Lucia Valentino, Valerio Carelli, Serenella Servidei, Steven S Gross, Giovanni Manfredi, Qiuying Chen, Marilena D'Aurelio.

  Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.

Keywords:  amino acid metabolism; glucocorticoids; leptin; mitochondrial myopathy; muscle wasting

DOI:  https://doi.org/10.15252/emmm.202216951
EMBO J. 2023 May 25. e112817

Host cell egress of Brucella abortus requires BNIP3L-mediated mitophagy.

Jérémy Verbeke, Youri Fayt, Lisa Martin, Oya Yilmaz, Jaroslaw Sedzicki, Angéline Reboul, Michel Jadot, Patricia Renard, Christoph Dehio, Henri-François Renard, Jean-Jacques Letesson, Xavier De Bolle, Thierry Arnould.

  The facultative intracellular pathogen Brucella abortus interacts with several organelles of the host cell to reach its replicative niche inside the endoplasmic reticulum. However, little is known about the interplay between the intracellular bacteria and the host cell mitochondria. Here, we showed that B. abortus triggers substantive mitochondrial network fragmentation, accompanied by mitophagy and the formation of mitochondrial Brucella-containing vacuoles during the late steps of cellular infection. Brucella-induced expression of the mitophagy receptor BNIP3L is essential for these events and relies on the iron-dependent stabilisation of the hypoxia-inducible factor 1α. Functionally, BNIP3L-mediated mitophagy appears to be advantageous for bacterial exit from the host cell as BNIP3L depletion drastically reduces the number of reinfection events. Altogether, these findings highlight the intricate link between Brucella trafficking and the mitochondria during host cell infection.

Keywords:   Brucella ; BNIP3L; intracellular trafficking; iron; mitophagy

DOI:  https://doi.org/10.15252/embj.2022112817
EMBO J. 2023 May 23. e112542

Coronaviral ORF6 protein mediates inter-organelle contacts and modulates host cell lipid flux for virus production.

Mengzhen Yue, Bing Hu, Jiajia Li, Ruifeng Chen, Zhen Yuan, Hurong Xiao, Haishuang Chang, Yaming Jiu, Kun Cai, Binbin Ding.

  Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance β-oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria-LD and ER-LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER-LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.

Keywords:  ORF6; endoplasmic reticulum; lipid droplets; mitochondria; organelle interaction

DOI:  https://doi.org/10.15252/embj.2022112542
Nat Commun. 2023 May 24. 14(1): 2847

Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.

Zoë P Van Acker, Anika Perdok, Ruben Hellemans, Katherine North, Inge Vorsters, Cedric Cappel, Jonas Dehairs, Johannes V Swinnen, Ragna Sannerud, Marine Bretou, Markus Damme, Wim Annaert.

Phospholipase D3 (PLD3) polymorphisms are linked to late-onset Alzheimer's disease (LOAD). Being a lysosomal 5'-3' exonuclease, its neuronal substrates remained unknown as well as how a defective lysosomal nucleotide catabolism connects to AD-proteinopathy. We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells. mtDNA accretion creates a degradative (proteolytic) bottleneck that presents at the ultrastructural level as a marked abundance of multilamellar bodies, often containing mitochondrial remnants, which correlates with increased PINK1-dependent mitophagy. Lysosomal leakage of mtDNA to the cytosol activates cGAS-STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation. STING inhibition largely normalizes APP-CTF levels, whereas an APP knockout in PLD3-deficient backgrounds lowers STING activation and normalizes cholesterol biosynthesis. Collectively, we demonstrate molecular cross-talks through feedforward loops between lysosomal nucleotide turnover, cGAS-STING and APP metabolism that, when dysregulated, result in neuronal endolysosomal demise as observed in LOAD.

DOI: https://doi.org/10.1038/s41467-023-38501-w
Circ Res. 2023 May 26.

Distinct Roles of DRP1 in Conventional and Alternative Mitophagy in Obesity Cardiomyopathy.

Mingming Tong, Risa Mukai, Satvik Mareedu, Peiyong Zhai, Shin-Ichi Oka, Chun-Yang Huang, Chiao-Po Hsu, Fawad A K Yousufzai, Luke Fritzky, Wataru Mizushima, Gopal J Babu, Junichi Sadoshima.

   RATIONALE: Obesity induces cardiomyopathy characterized by hypertrophy and diastolic dysfunction. Whereas mitophagy mediated through an Atg7-dependent mechanism serves as an essential mechanism to maintain mitochondrial quality during the initial development of obesity cardiomyopathy, Rab9-dependent alternative mitophagy takes over the role during the chronic phase. Although it has been postulated that DRP1 (dynamin-related protein 1)-mediated mitochondrial fission and consequent separation of the damaged portions of mitochondria are essential for mitophagy, the involvement of DRP1 in mitophagy remains controversial.
OBJECTIVE: We investigated whether endogenous DRP1 is essential in mediating the 2 forms of mitophagy during high-fat diet (HFD)-induced obesity cardiomyopathy and, if so, what the underlying mechanisms are.
METHODS AND RESULTS: Mice were fed either a normal diet or an HFD (60 kcal %fat). Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD consumption. The induction of mitophagy by HFD consumption was completely abolished in tamoxifen-inducible cardiac-specific Drp1knockout (Drp1 MCM) mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. The increase in LC3-dependent general autophagy and colocalization between LC3 and mitochondrial proteins was abolished in Drp1 MCM mice. Activation of alternative mitophagy was also completely abolished in Drp1 MCM mice during the chronic phase of HFD consumption. DRP1 was phosphorylated at Ser616, localized at the mitochondria-associated membranes, and associated with Rab9 and Fis1 only during the chronic, but not acute, phase of HFD consumption.
CONCLUSIONS: DRP1 is an essential factor in mitochondrial quality control during obesity cardiomyopathy that controls multiple forms of mitophagy. Although DRP1 regulates conventional mitophagy through a mitochondria-associated membrane-independent mechanism during the acute phase, it acts as a component of the mitophagy machinery at the mitochondria-associated membranes in alternative mitophagy during the chronic phase of HFD consumption.

Keywords:  diet, high-fat; mice, knockout; mitochondria; mitophagy; obesity cardiomyopathy

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.322512
Antioxid Redox Signal. 2023 May 22.

Mitochondrial dynamics and cristae shape changes during metabolic reprogramming.

Ippei Kawano, Bazila Bazila, Petr Jezek, Andrea Dlasková.

SIGNIFICANCE: The architecture of the mitochondrial network and cristae critically impact cell differentiation and identity. Cells undergoing metabolic reprogramming to aerobic glycolysis (Warburg effect), such as immune cells, stem cells, and cancer cells, go through controlled modifications in mitochondrial architecture, which is critical for achieving the resulting cellular phenotype.
RECENT ADVANCES: Recent studies in immunometabolism have shown that the manipulation of mitochondrial network dynamics and cristae shape directly affects T cell phenotype and macrophage polarization through altering energy metabolism. Similar manipulations also alter the specific metabolic phenotypes that accompany somatic reprogramming, stem cell differentiation, and cancer cells. The modulation of OXPHOS activity, accompanied by changes in metabolite signaling, ROS generation, and ATP levels is the shared underlying mechanism.
CRITICAL ISSUES: The plasticity of mitochondrial architecture is particularly vital for metabolic reprogramming. Consequently, failure to adapt the appropriate mitochondrial morphology often compromises the differentiation and identity of the cell. Immune, stem, and tumor cells exhibit striking similarities in their coordination of mitochondrial morphology with metabolic pathways. However, although many general unifying principles can be observed, their validity is not absolute, and the mechanistic links thus need to be further explored.
FUTURE DIRECTIONS: Better knowledge of the molecular mechanisms involved and their relationships to both mitochondrial network and cristae morphology will not only further deepen our understanding of energy metabolism but may also contribute to improved therapeutic manipulation of cell viability, differentiation, proliferation, and identity in many different cell types.

DOI: https://doi.org/10.1089/ars.2023.0268