Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.

Low pyruvate carboxylase expression creates asparagine dependency in respiration-compromised cells with high mtDNA heteroplasmy, with translational defects above 70% that asparagine or PC can reverse.

• Why it matters: mtDNA mutations impair oxidative phosphorylation, but it is unclear whether higher heteroplasmy introduces new metabolic dependencies absent in respiratory-competent cells.
• What they did: Using isogenic cells with similar mtDNA deletions, the study measured how respiration, redox imbalance, and integrated stress-response-linked translational defects change with heteroplasmy, then tested rescue by exogenous asparagine or PC overexpression.
• The result: Asparagine dependence inversely correlated with PC expression and matched patient-derived thyroid tumour cells with high-heteroplasmy complex I mutations and low PC, which showed asparagine auxotrophy and L-asparaginase sensitivity.

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