SUMMARY Stress-regulated signaling pathways protect mitochondrial proteostasis, and thus mitochondrial function, from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. Here, we identify Tim17A as a stress-regulated subunit of the Translocase of the Inner Membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eIF2α phosphorylation through a mechanism dependent on the mitochondrial protease YME1L. Furthermore, we demonstrate that decreasing Tim17A protein levels attenuates TIM23-dependent protein import, promotes the induction of mitochondrial Unfolded Protein Response-associated proteostasis genes, and confers stress-resistance in C. elegans and mammalian cells. Thus, our results indicate that Tim17A degradation is a stress-responsive mechanism by which cells adapt mitochondrial protein import efficiency and promote mitochondrial proteostasis in response to the numerous pathologic insults that induce stress-regulated translation attenuation.

SUMMARY The mitochondrial inner membrane proteases YME1L and OMA1 are critical regulators of essential mitochondrial functions including inner membrane proteostasis maintenance and mitochondrial dynamics. Here, we show that YME1L and OMA1 are reciprocally degraded in response to distinct types of cellular stress. OMA1 is degraded through a YME1L-dependent mechanism in response to toxic insults that depolarize the mitochondrial membrane. Alternatively, insults that depolarize mitochondria and deplete cellular ATP stabilize active OMA1 and promote YME1L degradation. We show that the differential degradation of YME1L and OMA1 alters their proteolytic processing of the dynamin-like GTPase OPA1, a critical regulator of mitochondrial inner membrane morphology, which influences the recovery of tubular mitochondria following membrane depolarization-induced fragmentation. Our results reveal the differential stress-induced degradation of YME1L and OMA1 as a mechanism to sensitively adapt mitochondrial inner membrane protease activity and function in response to distinct types of cellular insults.

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SUMMARY The spread of mosquito-borne Zika virus (ZIKV), which causes neurological disorders and micro-cephaly, highlights the need for countermeasures against sudden viral epidemics. Here, we tested the concept that drugs targeting host proteostasis pro-vide effective antivirals. We show that different cyto-solic Hsp70 isoforms are recruited to ZIKV-induced compartments and are required for virus replication at pre- and post-entry steps. Drugs targeting Hsp70 significantly reduce replication of different ZIKV strains in human and mosquito cells, including hu-man neural stem cells and a placental trophoblast cell line, at doses without appreciable toxicity to the host cell. By targeting several ZIKV functions, including entry, establishment of active replication complexes, and capsid assembly, Hsp70 inhibitors are refractory to the emergence of drug-resistant virus. Importantly, these drugs protected mouse models from ZIKV infection, reducing viremia, mor-tality, and disease symptoms. Hsp70 inhibitors are thus attractive candidates for ZIKV therapeutics with the added benefit of a broad spectrum of action.