Metabolic Compensation Associated with Progressive Mitochondrial Dysfunction

The decline in mitochondrial function has been associated and correlated with aging and various neurogenerative diseases. The mitochondria lie at a critical junction of several metabolic pathways, and metabolic reactions are highly compartmentalized across distinct tissues. As such, progressive mitochondrial defects will have diverse metabolic and phenotypic consequences that could reflect physiological changes that occur with aging. Here, we comprehensively characterized metabolic alterations in Polg D257A mitochondrial DNA mutator mice throughout the aging process. Plasma alanine increased dramatically with progressive loss of mitochondria, with lactate and other organic acids accumulating to a lesser extent. These changes are reflective of an increased glycolytic flux and rapid glucose turnover, and a reduced ability to oxidize keto acids, as demonstrated by [ 13 C]glucose tracing. Amino acid changes were also suggestive of dysfunctional nitrogen metabolism, which was confirmed by quantifying [ 15 N]ammonium incorporation into urea and amino acids. Additionally, progressive mitochondrial dysfunction led to alterations in the lipidome including sphingolipids. We observed the accumulation of 1‐deoxysphingolipids, which are synthesized by serine palmitoyltransferase (SPT) using alanine. Consistent with this metabolic rewiring, Polg D257A mice exhibit accelerated thermal hypoalgesia. These results highlight the distinct changes that occur in carbon and nitrogen metabolism upon mitochondrial loss and highlight key metabolic mechanisms which can drive aging associated neuropathy.