Cardioprotection by the mitochondrial unfolded protein response requires ATF5

Abstract

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. UPRmt activation upregulates chaperones, proteases, antioxidants, and glycolysis at the gene level to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5) is a proposed mediator of the mammalian UPRmt. Herein, we hypothesized pharmacological UPRmt activation may protect against cardiac ischemia-reperfusion (I/R) injury in an ATF5-dependent manner. Accordingly, in vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h before ex vivo I/R injury (perfused heart) was cardioprotective in wild-type but not global Atf5−/− mice. Acute ex vivo UPRmt activation was not cardioprotective, and loss of ATF5 did not impact baseline I/R injury without UPRmt induction. In vivo UPRmt induction significantly upregulated many known UPRmt-linked genes (cardiac quantitative PCR and Western blot analysis), and RNA-Seq revealed an UPRmt-induced ATF5-dependent gene set, which may contribute to cardioprotection. This is the first in vivo proof of a role for ATF5 in the mammalian UPRmt and the first demonstration that UPRmt is a cardioprotective drug target. NEW & NOTEWORTHY Cardioprotection can be induced by drugs that activate the mitochondrial unfolded protein response (UPRmt). UPRmt protection is dependent on activating transcription factor 5 (ATF5). This is the first in vivo evidence for a role of ATF5 in the mammalian UPRmt.

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

“…Based on all this information, we speculate that a branch of UPR mt induced by ATFS-1 activation is directly involved in the protection from alcohol-mediated muscle dysfunction. Interestingly, although we do not know that UPR mt influences alcohol-induced tissue damage, several studies in mammals indeed showed that UPR mt upregulation is protective from certain stress-induced organ damage (41)(42)(43). Taken together, we propose that mitochondrial dysfunction and consequent UPR mt activation may underlie many pathologies of alcoholic myopathy and further understanding of UPR mt in alcoholic myopathy may lead to a better therapeutic intervention.…”

Alcohol induces mitochondrial fragmentation and stress responses to maintain normal muscle function in Caenorhabditis elegans

“…Based on this information, we speculate that UPR mt induced by ATFS‐1 activation is directly involved in protection against alcohol‐mediated muscle dysfunction. Interestingly, although we do not know if UPR mt influences alcohol‐induced tissue damage, several studies in mammals have indeed shown that UPR mt upregulation is protective against certain types of stress‐induced organ damage 58‐60 . Studies in both C elegans and mammals showed that UPR mt promotes mitochondrial protein homeostasis, increases mitochondrial protein import, confers innate immunity, and reorganizes metabolic enzymes 11,61‐63 .…”

Integrating ER and Mitochondrial Proteostasis in the Healthy and Diseased Heart

“…In the same study it was also shown that hearts from patients with aortic stenosis, which is often associated with left ventricular overload, exhibited increased expression of genes associated with the UPR mt . In another study, mice in which ATF5 was genetically deleted were used to show that the UPR mt protected the heart against I/R in an ATF5-dependent manner (53). Moreover, in the same study RNAseq results demonstrated the induction of numerous genes in an ATF5-dependent manner during pharmacological induction of the UPR mt .…”

“…Upon accumulation ATF5 is then exported from mitochondria to the nucleus where it acts as a transcription factor that induces genes encoding proteins designed to improve mitochondrial protein folding and rebalance mitochondrial proteostasis (Figure 1F), such as HSPA9, LonP1, and YME1L. ATF5 also serves as a communicator of metabolic stress by temporarily limiting the transcription of OXPHOS genes encoded in nuclear and mitochondrial genomes, while simultaneously increasing nuclear encoded gene transcription of all glycolysis components, and this is thought to maintain cellular ATP levels until mitochondrial dysfunction is resolved (45,53).…”