An amino acid polymorphism in the Rad2/XPG protein Mkt1 (Mkt1-G30D) reportedly underlies variation in mitochondrial phenotypes among laboratory yeast, but the function of Mkt1 and the effects of the polymorphism are unknown. We confirm with genetics and biochemical assays guided by AlphaFold structure predictions that Mkt1 forms a complex with Pbp1, a messenger RNP protein that supports adaptations to respiratory conditions, such as Pumilio protein Puf3-dependent mitochondrial protein expression and TORC1-dependent autophagy. Using CEN.PK (Mkt1-G30) yeast, we show that, like Pbp1, Mkt1 is required for Puf3-dependent mitochondrial protein expression and autophagy during respiratory growth. Notably, we found the Mkt1-G30D mutation destabilizes the Mkt1/Pbp1 complex, helping to explain its loss-of-function effects. A HAP1+ S288C strain exhibited defects in mitochondrial biogenesis and autophagy, which were rescued by replacing its Mkt1-D30 allele with the Mkt1-G30 allele. Thus, the Mkt1/Pbp1 complex supports adaptive processes during respiratory growth, and the Mkt1-G30D mutation is an evolutionary adaptation that tempers respiratory processes by destabilizing the Mkt1/Pbp1 complex.

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Journal Article

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Caballero D, Sutter BM, Xing Z, Wang C, Choo E, Wang Y, Yang YS, Ghaemmaghami S, Lemoff A, Tu BP

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