Progressive alterations in amino acid and lipid metabolism correlate with peripheral neuropathy in <i>Polg</i><sup>D257A</sup> mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34652935.
- Also identified by DOI 10.1126/sciadv.abj4077 and PMC identifier 8519573.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Mitochondria are central to metabolic homeostasis, and progressive mitochondrial defects have diverse metabolic consequences that could drive distinct pathophysiological states. Here, we comprehensively characterized metabolic alterations in <i>Polg</i><sup>D257A</sup> mice. Plasma alanine increased markedly with time, with other organic acids accumulating to a lesser extent. These changes were reflective of increased Cori and Cahill cycling in <i>Polg</i><sup>D257A</sup> mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [<sup>15</sup>N]ammonium further supported this shift in amino acid metabolism with mild impairment of the urea cycle. We also measured alterations in the lipidome, observing a reduction in canonical lipids and accumulation of 1-deoxysphingolipids, which are synthesized from alanine via promiscuous serine palmitoyltransferase activity and correlate with peripheral neuropathy. Consistent with this metabolic link, <i>Polg</i><sup>D257A</sup> mice exhibited thermal hypoalgesia. These results highlight the longitudinal changes that occur in intermediary metabolism upon mitochondrial impairment and identify a contributing mechanism to mitochondria-associated neuropathy.