Altered Steroidogenesis in Response to Impaired Mitochondrial Protein Homeostasis

Mitochondrial proteostasis is critical for organelle function, but how it influences mitochondrial steroidogenesis is not understood. We investigated the impact of impaired mitochondrial proteostasis on mitochondrial protein import and how this impacts cortisol production. We found that mild mitochondrial proteostatic stress increased cortisol synthesis whereas severe stress suppressed cortisol, revealing a biphasic steroidogenic response. Mild stress induced increases in cholesterol import and cortisol production in a manner dependent on STARD1-mediated cholesterol transport, which is the first and rate-limiting step in steroidogenesis. Severe stress reduced cortisol synthesis independently of STARD1 activity, indicating this inhibition occurs downstream in steroidogenesis. These findings reveal mitochondrial protein import as a regulatory node linking mitochondrial proteostasis to steroidogenic output. Furthermore, we observed increased cortisol synthesis in rotenone, A53T alpha-synuclein and PINK1-KO models of PD, suggesting that this response is relevant to PD-associated mitochondrial dysfunction. Together, our findings reveal a biphasic steroidogenic response to impairments in mitochondrial quality control with implications in human disease. Our work recognizes a previously unexplored branch of the mitochondrial stress response that enables cellular and physiological adaptations that can be detrimental if constitutively activated.