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 Polg^D257A 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 Polg^D257A mice and subsequent hypoglycemia, which did not occur during normal mouse aging. Tracing with [¹⁵N]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, Polg^D257A 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.