Mitochondrial Localization and Abundance of Leishmania Cytochrome c Oxidase Subunit IV Is Maintained Following Loss of Mitochondrial Membrane Potential Associated With Mammalian Temperature

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ABSTRACT In eukaryotes, exposure to elevated temperature can disrupt cellular activities, including mitochondrial membrane potential (ΔΨm). Among multiple impacts, loss of ΔΨm typically results in mislocalization of nuclear‐encoded mitochondria‐destined proteins followed by their proteostatic degradation. As part of their natural transmission cycle, Leishmania encounter an abrupt temperature increase when inoculated into mammalian hosts via the bite of phlebotomine sandflies. How Leishmania maintain mitochondrial protein import in the face of this heat stress remains unknown. We therefore examined the relationship between ΔΨm, abundance of L. major cytochrome c oxidase complex subunit IV (LmCOX4) and its cellular localization functions at insect and mammalian temperatures. Intriguingly, LmCOX4 contains both a mitochondrial targeting sequence (MTS LmCOX4 ) and a PTS‐1 glycosomal targeting motif. LmCOX4 is transiently down‐modulated following exposure to mammalian temperature, suggesting that heat‐induced loss of ΔΨm could lead to LmCOX4 mislocalization and degradation. We find, however, that while transient down‐modulation of LmCOX4 promotes viability at mammalian temperature, the associated loss of ΔΨm impacts neither MTS LmCOX4 ‐mediated localization nor LmCOX4 abundance. Unexpectedly, the canonical positive charges of MTS LmCOX4 are dispensable for mitochondrial localization. Further, LmCOX4's glycosomal targeting sequence has no apparent role in cellular localization at insect or mammalian temperatures.

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