bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2023–10–29
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Lactate activates the mitochondrial electron transport chain independently of its metabolism.
  2. Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
  1. Mol Cell. 2023 Oct 20. pii: S1097-2765(23)00800-6. [Epub ahead of print]
    Lactate activates the mitochondrial electron transport chain independently of its metabolism.
    Xin Cai, Charles P Ng, Olivia Jones, Tak Shun Fung, Keun Woo Ryu, Dayi Li, Craig B Thompson.
      Lactate has long been considered a cellular waste product. However, we found that as extracellular lactate accumulates, it also enters the mitochondrial matrix and stimulates mitochondrial electron transport chain (ETC) activity. The resulting increase in mitochondrial ATP synthesis suppresses glycolysis and increases the utilization of pyruvate and/or alternative respiratory substrates. The ability of lactate to increase oxidative phosphorylation does not depend on its metabolism. Both L- and D-lactate are effective at enhancing ETC activity and suppressing glycolysis. Furthermore, the selective induction of mitochondrial oxidative phosphorylation by unmetabolized D-lactate reversibly suppressed aerobic glycolysis in both cancer cell lines and proliferating primary cells in an ATP-dependent manner and enabled cell growth on respiratory-dependent bioenergetic substrates. In primary T cells, D-lactate enhanced cell proliferation and effector function. Together, these findings demonstrate that lactate is a critical regulator of the ability of mitochondrial oxidative phosphorylation to suppress glucose fermentation.
    Keywords:  TCA cycle; electron transport chain; glycolysis; lactate; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.034
  2. Redox Biol. 2023 Oct 17. pii: S2213-2317(23)00333-6. [Epub ahead of print]67 102932
    Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
    Gerardo G Piroli, Allison M Manuel, Richard S McCain, Holland H Smith, Oliver Ozohanics, Sara Mellid, J Hunter Cox, William E Cotham, Michael D Walla, Alberto Cascón, Attila Ambrus, Norma Frizzell.
      The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.
    Keywords:  Alpha-ketoglutarate dehydrogenase; Complex I; Fumarate; Leigh syndrome; Protein succination; Substrate level phosphorylation
    DOI:  https://doi.org/10.1016/j.redox.2023.102932
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