bims-smemid 2023-08-06 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2023–08–06
five papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

Inter-tissue communication of mitochondrial stress and metabolic health.
Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.
Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
FACT regulates pluripotency through proximal and distal regulation of gene expression in murine embryonic stem cells.
Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Life Metab. 2023 Feb;pii: load001. [Epub ahead of print]2(1):

Inter-tissue communication of mitochondrial stress and metabolic health.

Hanlin Zhang, Xinyu Li, Wudi Fan, Sentibel Pandovski, Ye Tian, Andrew Dillin.

  Mitochondria function as a hub of the cellular metabolic network. Mitochondrial stress is closely associated with aging and a variety of diseases, including neurodegeneration and cancer. Cells autonomously elicit specific stress responses to cope with mitochondrial stress to maintain mitochondrial homeostasis. Interestingly, mitochondrial stress responses may also be induced in a non-autonomous manner in cells or tissues that are not directly experiencing such stress. Such non-autonomous mitochondrial stress responses are mediated by secreted molecules called mitokines. Due to their significant translational potential in improving human metabolic health, there has been a surge in mitokine-focused research. In this review, we summarize the findings regarding inter-tissue communication of mitochondrial stress in animal models. In addition, we discuss the possibility of mitokine-mediated intercellular mitochondrial communication originating from bacterial quorum sensing.

Keywords:  inter-tissue communication; metabolic health; mitochondria; mitokine; quorum sensing

DOI:  https://doi.org/10.1093/lifemeta/load001
Cell Rep. 2023 Jul 29. pii: S2211-1247(23)00857-4. [Epub ahead of print]42(8): 112846

Phospholipids can regulate complex I assembly independent of their role in maintaining mitochondrial membrane integrity.

Anjaneyulu Murari, Shauna-Kay Rhooms, Divya Vimal, Kaniz Fatima Binte Hossain, Sanjay Saini, Maximino Villanueva, Michael Schlame, Edward Owusu-Ansah.

  Several phospholipid (PL) molecules are intertwined with some mitochondrial complex I (CI) subunits in the membrane domain of CI, but their function is unclear. We report that when the Drosophila melanogaster ortholog of the intramitochondrial PL transporter, STARD7, is severely disrupted, assembly of the oxidative phosphorylation (OXPHOS) system is impaired, and the biogenesis of several CI subcomplexes is hampered. However, intriguingly, a restrained knockdown of STARD7 impairs the incorporation of NDUFS5 and NDUFA1 into the proximal part of the CI membrane domain without directly affecting the incorporation of subunits in the distal part of the membrane domain, OXPHOS complexes already assembled, or mitochondrial cristae integrity. Importantly, the restrained knockdown of STARD7 appears to induce a modest amount of cardiolipin remodeling, indicating that there could be some alteration in the composition of the mitochondrial phospholipidome. We conclude that PLs can regulate CI biogenesis independent of their role in maintaining mitochondrial membrane integrity.

Keywords:  CP: Molecular biology; Drosophila; NDUFA1; NDUFS5; OXPHOS; STARD7; complex I; mitochondria; phospholipid

DOI:  https://doi.org/10.1016/j.celrep.2023.112846
EMBO Mol Med. 2023 Aug 03. e17399

Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.

Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.

  Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin

DOI:  https://doi.org/10.15252/emmm.202317399
BMC Biol. 2023 Aug 04. 21(1): 167

FACT regulates pluripotency through proximal and distal regulation of gene expression in murine embryonic stem cells.

David C Klein, Santana M Lardo, Kurtis N McCannell, Sarah J Hainer.

   BACKGROUND: The FACT complex is a conserved histone chaperone with critical roles in transcription and histone deposition. FACT is essential in pluripotent and cancer cells, but otherwise dispensable for most mammalian cell types. FACT deletion or inhibition can block induction of pluripotent stem cells, yet the mechanism through which FACT regulates cell fate decisions remains unclear.
RESULTS: To explore the mechanism for FACT function, we generated AID-tagged murine embryonic cell lines for FACT subunit SPT16 and paired depletion with nascent transcription and chromatin accessibility analyses. We also analyzed SPT16 occupancy using CUT&RUN and found that SPT16 localizes to both promoter and enhancer elements, with a strong overlap in binding with OCT4, SOX2, and NANOG. Over a timecourse of SPT16 depletion, nucleosomes invade new loci, including promoters, regions bound by SPT16, OCT4, SOX2, and NANOG, and TSS-distal DNaseI hypersensitive sites. Simultaneously, transcription of Pou5f1 (encoding OCT4), Sox2, Nanog, and enhancer RNAs produced from these genes' associated enhancers are downregulated.
CONCLUSIONS: We propose that FACT maintains cellular pluripotency through a precise nucleosome-based regulatory mechanism for appropriate expression of both coding and non-coding transcripts associated with pluripotency.

Keywords:  Chromatin; Embryonic stem cells; FACT; Genomics; Histone chaperone; Histones; Nucleosome; Pluripotency; RNA; Transcription

DOI:  https://doi.org/10.1186/s12915-023-01669-0
Mol Neurobiol. 2023 Jul 31.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Dhivya Venkatesan, Mahalaxmi Iyer, Arul Narayanasamy, Abilash Valsala Gopalakrishnan, Balachandar Vellingiri.

  Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Keywords:  Copy number; Mitochondrial DNA; Molecular pathways; Parkinson’s disease; TFAM; Therapeutic strategies

DOI:  https://doi.org/10.1007/s12035-023-03500-x