bims-smemid Biomed News
on Stress metabolism in mitochondrial dysfunction
Issue of 2024–01–28
two papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines
  1. Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
  2. Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.
  1. Geroscience. 2024 Jan 25.
    Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation.
    Roman Abrosimov, Marius W Baeken, Samuel Hauf, Ilka Wittig, Parvana Hajieva, Carmen E Perrone, Bernd Moosmann.
      Inhibition of mitochondrial complex I (NADH dehydrogenase) is the primary mechanism of the antidiabetic drug metformin and various unrelated natural toxins. Complex I inhibition can also be induced by antidiabetic PPAR agonists, and it is elicited by methionine restriction, a nutritional intervention causing resistance to diabetes and obesity. Still, a comprehensible explanation to why complex I inhibition exerts antidiabetic properties and engenders metabolic inefficiency is missing. To evaluate this issue, we have systematically reanalyzed published transcriptomic datasets from MPP-treated neurons, metformin-treated hepatocytes, and methionine-restricted rats. We found that pathways leading to NADPH formation were widely induced, together with anabolic fatty acid biosynthesis, the latter appearing highly paradoxical in a state of mitochondrial impairment. However, concomitant induction of catabolic fatty acid oxidation indicated that complex I inhibition created a "futile" cycle of fatty acid synthesis and degradation, which was anatomically distributed between adipose tissue and liver in vivo. Cofactor balance analysis unveiled that such cycling would indeed be energetically futile (-3 ATP per acetyl-CoA), though it would not be redox-futile, as it would convert NADPH into respirable FADH2 without any net production of NADH. We conclude that inhibition of NADH dehydrogenase leads to a metabolic shift from glycolysis and the citric acid cycle (both generating NADH) towards the pentose phosphate pathway, whose product NADPH is translated 1:1 into FADH2 by fatty acid cycling. The diabetes-resistant phenotype following hepatic and intestinal complex I inhibition is attributed to FGF21- and GDF15-dependent fat hunger signaling, which remodels adipose tissue into a glucose-metabolizing organ.
    Keywords:  Diabetes; FGF21; Metformin; Methionine restriction; NADH dehydrogenase; Peroxisome proliferator-activated receptor
    DOI:  https://doi.org/10.1007/s11357-023-01059-y
  2. bioRxiv. 2024 Jan 01. pii: 2023.12.31.573776. [Epub ahead of print]
    Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.
    Anthony R P Verkerke, Xu Shi, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.
      Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo . We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival.
    Key points: SLC25A48 is required for mitochondrial choline uptake.Mitochondrial choline uptake regulates one-carbon contribution to purine nucleotide synthesis.Brown fat thermogenesis requires mitochondrial choline catabolism for respiratory capacity.Cancer cells require mitochondrial choline uptake for cell survival.
    DOI:  https://doi.org/10.1101/2023.12.31.573776
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