Mitochondrial localization and regulation of Leishmania Cytochrome C Oxidase Subunit IV during mammalian temperature adaptation

Candidate

• Isabel Stephany-Brassesco, LSU Health New OrleansFollow

Examination Date

Spring 3-30-2026

Degree

Dissertation

Degree Program

Microbiology, Immunology and Parasitology

Examination Committee

Ben Kelly, Jennifer Cameron, Edward Wojcik, Dug Johnston, Joy Sturtevant

Abstract

Leishmania parasites undergo extensive physiological remodeling during transition from the sand fly vector to the mammalian host, where elevated temperature, acidic pH, and host-associated stress require rapid adaptation for survival and virulence. This dissertation investigates regulation of the nuclear-encoded cytochrome c oxidase subunit IV homolog, LCOX4, during adaptation to mammalian temperature and examines its contribution to mitochondrial function and parasite fitness.

LCOX4 expression was analyzed during exposure to mammalian temperature in multiple Leishmania  species. In each case, LCOX4 abundance decreased transiently following temperature shift and recovered at later time points, indicating that its expression is dynamically regulated during thermal adaptation rather than constitutively maintained. This period of reduced expression coincided with decreased cellular ATP levels, consistent with early energetic stress.

Because mitochondrial membrane potential (ΔΨm) is required for import of many nuclear-encoded mitochondrial proteins, this dissertation also tested whether transient LCOX4 loss resulted from impaired mitochondrial targeting. Although mammalian temperature caused substantial mitochondrial depolarization, LmCOX4 retained mitochondrial localization, and disruption of canonical positively charged residues within its predicted mitochondrial targeting sequence did not abolish import. These findings indicate that transient loss of endogenous LCOX4 is unlikely to result from failure of mitochondrial import.

Further analyses showed that constitutively expressed episomal LCOX4 did not undergo the same temperature-dependent decline as endogenous LCOX4, supporting a model in which regulation occurs upstream of import, potentially through post-transcriptional mechanisms such as transcript stability or translation. Importantly, forced maintenance of LCOX4 expression reduced parasite fitness at mammalian temperature. Together, these findings identify LCOX4 as a dynamically regulated determinant of mitochondrial remodeling during adaptation of Leishmania to the mammalian host.

Recommended Citation

Stephany-Brassesco, Isabel, "Mitochondrial localization and regulation of Leishmania Cytochrome C Oxidase Subunit IV during mammalian temperature adaptation" (2026). School of Graduate Studies. 23.
https://digitalscholar.lsuhsc.edu/etd_sgs/23