bims-mitdyn 2024-12-01 papers

Nat Chem Biol. 2024 Nov 28.

Mitochondria-localized MBD2c facilitates mtDNA transcription and drug resistance.

Yijie Hao, Zilong Zhou, Rui Liu, Shengqi Shen, Haiying Liu, Yingli Zhou, Yuchen Sun, Qiankun Mao, Tong Zhang, Shi-Ting Li, Zhaoji Liu, Yiyang Chu, Linchong Sun, Ping Gao, Huafeng Zhang.

Mitochondria contain a 16-kb double stranded DNA genome encoding 13 proteins essential for respiration, but the mechanisms regulating transcription and their potential role in cancer remain elusive. Although methyl-CpG-binding domain (MBD) proteins are essential for nuclear transcription, their role in mitochondrial DNA (mtDNA) transcription is unknown. Here we report that the MBD2c splicing variant translocates into mitochondria to mediate mtDNA transcription and increase mitochondrial respiration in triple-negative breast cancer (TNBC) cells. In particular, MBD2c binds the noncoding region in mtDNA and interacts with SIRT3, which in turn deacetylates and activates TFAM, a primary mitochondrial transcription factor, leading to enhanced mtDNA transcription. Furthermore, MBD2c recovered the decreased mitochondrial gene expression caused by the DNA synthesis inhibitor cisplatin, preserving mitochondrial respiration and consequently enhancing drug resistance and proliferation in TNBC cells. These data collectively demonstrate that MBD2c positively regulates mtDNA transcription, thus connecting epigenetic regulation by deacetylation with cancer cell metabolism, suggesting druggable targets to overcome resistance.

DOI: https://doi.org/10.1038/s41589-024-01776-1

Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.

Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.

The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

Keywords: ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response

DOI: https://doi.org/10.1073/pnas.2410486121

Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2416882121

PGC-1α drives small cell neuroendocrine cancer progression toward an ASCL1-expressing subtype with increased mitochondrial capacity.

Adenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.

Keywords: ASCL1; PGC-1a; lung cancer; oxidative phosphorylation; prostate cancer

DOI: https://doi.org/10.1073/pnas.2416882121

Cell Death Dis. 2024 Nov 24. 15(11): 856

Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.

Yizhou Yu, Civia Z Chen, Ivana Celardo, Bryan Wei Zhi Tan, James D Hurcomb, Nuno Santos Leal, Rebeka Popovic, Samantha H Y Loh, L Miguel Martins.

Alzheimer's disease (AD) is the most common form of age-related dementia. In AD, the death of neurons in the central nervous system is associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. Mitochondria are signal transducers of metabolic and biochemical information, and their impairment can compromise cellular function. Mitochondria compartmentalise several pathways, including folate-dependent one-carbon (1C) metabolism and electron transport by respiratory complexes. Mitochondrial 1C metabolism is linked to electron transport through complex I of the respiratory chain. Here, we analysed the proteomic changes in a fly model of AD by overexpressing a toxic form of Aβ (Aβ-Arc). We found that expressing Aβ-Arc caused alterations in components of both complex I and mitochondrial 1C metabolism. Genetically enhancing mitochondrial 1C metabolism through Nmdmc improved mitochondrial function and was neuroprotective in fly models of AD. We also found that exogenous supplementation with the 1C donor folinic acid improved mitochondrial health in both mammalian cells and fly models of AD. We found that genetic variations in MTHFD2L, the human orthologue of Nmdmc, were linked to AD risk. Additionally, Mendelian randomisation showed that increased folate intake decreased the risk of developing AD. Overall, our data suggest enhancement of folate-dependent 1C metabolism as a viable strategy to delay the progression and attenuate the severity of AD.

DOI: https://doi.org/10.1038/s41419-024-07179-3

Biochim Biophys Acta Mol Basis Dis. 2024 Nov 27. pii: S0925-4439(24)00561-1. [Epub ahead of print] 167567

Tissue-specific adaptations to cytochrome c oxidase deficiency shape physiological outcomes.

Milica Popovic, Lea Isermann, Simon Geißen, Katharina Senft, Theodoros Georgomanolis, Stephan Baldus, Christian Frezza, Aleksandra Trifunovic.

It becomes increasingly clear that the tissue specificity of mitochondrial diseases might in part rely on their ability to compensate for mitochondrial defects, contributing to the heterogeneous nature of mitochondrial diseases. Here, we investigated tissue-specific responses to cytochrome c oxidase (CIV or COX) deficiency using a mouse model with heart and skeletal muscle-specific depletion of the COX assembly factor COX10. At three weeks of age, both tissues exhibit pronounced CIV depletion but respond differently to oxidative phosphorylation (OXPHOS) impairment. Heart-specific COX10 depletion caused severe dilated cardiomyopathy, while skeletal muscle experiences less damage. Cardiac CIV deficiency triggered extensive metabolic remodelling and stress response activation, potentially worsening cardiomyopathy, whereas skeletal muscle showed no stress response or significant metabolic changes. Our findings highlight distinct tissue capacities for managing CIV deficiency, explaining how identical primary defects can lead to different phenotypic outcomes and contribute to the heterogeneous progression of mitochondrial diseases.

DOI: https://doi.org/10.1016/j.bbadis.2024.167567