Mitochondrial Stress Induces an HRI-eIF2α Pathway Protective for Cardiomyopathy

Zhu, Siting; Nguyen, Anh B.; Pang, Jing; Zhao, Jun; Chen, Zee; Liang, Zhengyu; Gu, Yusu; Huynh, Helen; Bao, Yutong; Lee, Sharon; Kluger, Yuval; Ouyang, Kunfu; Evans, Sylvia M.; Fang, Xi

doi:10.1161/circulationaha.122.059594

Cited by 15 publications

(7 citation statements)

References 5 publications

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“…We additionally found that the OMA1-dependent stress response is strongly protective in the IMMD model. Similar findings were independently reported for two other cardiomyopathy models (one from conditional knockout (KO) of a Complex IV subunit, COX10 (Ahola et al , 2022), and the other from KO of the cardiolipin remodeling protein Tafazzin (Huynh et al , 2022; Zhu et al , 2022)), together supporting the idea that the DELE1 mt-ISR mediates at least some mitochondria-to-nucleus signaling in response to mitochondrial stress in vivo . However, it is not known whether there is a common OMA1-DELE1 stress pathway responding to diverse mitochondrial stressors, such as protein unfolding and mtDNA maintenance.…”

Section: Introductionsupporting

confidence: 80%

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

Lin,

Petersen,

Gilsrud

et al. 2024

Preprint

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Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy. Here, we identified that diverse mitochondrial myopathy models elicit a protective mitochondrial integrated stress response (mt-ISR), mediated by OMA1-DELE1 signaling. The response was similar following disruptions in mtDNA maintenance, from knockout of Tfam, and mitochondrial protein unfolding, from disease-causing mutations in CHCHD10 (G58R and S59L). The preponderance of the response was directed at upregulating pathways for aminoacyl-tRNA biosynthesis, the intermediates for protein synthesis, and was similar in heart and skeletal muscle but more limited in brown adipose challenged with cold stress. Strikingly, models with early DELE1 mt-ISR activation failed to grow and survive to adulthood in the absence of Dele1, accounting for some but not all of OMA1's protection. Notably, the DELE1 mt-ISR did not slow net protein synthesis in stressed striated muscle, but instead prevented loss of translation-associated proteostasis in muscle fibers. Together our findings identify that the DELE1 mt-ISR mediates a stereotyped response to diverse forms of mitochondrial stress and is particularly critical for maintaining growth and survival in early-onset mitochondrial myopathy.

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Section: Introductionsupporting

confidence: 80%

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

Lin,

Petersen,

Gilsrud

et al. 2024

Preprint

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show abstract

“…This is in contrast with several recent publications reporting that HRI but not GCN2 is responsible for oligomycin-induced ISR activation, indicating that there might be a cell-type specific context at play that warrants further investigation. 28,86,87 Of note, while we have shown that ponatinib treatment compromises mitochondrial functions of hiPSC-CMs, further work is needed to unravel the exact mechanisms behind the mode of action underlying ponatinib-induced mitochondrial dysfunction, which may not be exactly identical to the direct use of complex I and V inhibitors in this study. Moreover, our results indicate that supplementation with NMN but not AAs or MitoTEMPO negated ponatinib-induced ISR activation, further suggesting that inhibition of ATP synthase is responsible for GCN2-mediated ISR activation instead of the canonical AA deficiency often associated with GCN2 activation.…”

Section: Discussionmentioning

confidence: 90%

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

Yan,

Han,

Kwon

et al. 2024

Circulation Research

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Background: Mitochondrial dysfunction is a primary driver of cardiac contractile failure; yet, the cross talk between mitochondrial energetics and signaling regulation remains obscure. Ponatinib, a tyrosine kinase inhibitor used to treat chronic myeloid leukemia, is among the most cardiotoxic tyrosine kinase inhibitors and causes mitochondrial dysfunction. Whether ponatinib-induced mitochondrial dysfunction triggers the integrated stress response (ISR) to induce ponatinib-induced cardiotoxicity remains to be determined. Methods: Using human-induced pluripotent stem cells–derived cardiomyocytes (hiPSC-CMs) and a recently developed mouse model of ponatinib-induced cardiotoxicity, we performed proteomic analysis, molecular and biochemical assays to investigate the relationship between ponatinib-induced mitochondrial stress and ISR and their role in promoting ponatinib-induced cardiotoxicity. Results: Proteomic analysis revealed that ponatinib activated the ISR in cardiac cells. We identified GCN2 (general control nonderepressible 2) as the eIF2α (eukaryotic translation initiation factor) kinase responsible for relaying mitochondrial stress signals to trigger the primary ISR effector—ATF4 (activating transcription factor 4), upon ponatinib exposure. Mechanistically, ponatinib treatment exerted inhibitory effects on ATP synthase activity and reduced its expression levels resulting in ATP deficits. Perturbed mitochondrial function resulting in ATP deficits then acts as a trigger of GCN2-mediated ISR activation, effects that were negated by nicotinamide mononucleotide, an NAD + precursor, supplementation. Genetic inhibition of ATP synthase also activated GCN2. Interestingly, we showed that the decreased abundance of ATP also facilitated direct binding of ponatinib to GCN2, unexpectedly causing its activation most likely because of a conformational change in its structure. Importantly, administering an ISR inhibition, ISRIB, protected human-induced pluripotent stem cell–derived cardiomyocytes against ponatinib. Ponatinib-treated mice also exhibited reduced cardiac function, effects that were attenuated upon systemic ISRIB administration. Importantly, ISRIB does not affect the antitumor effects of ponatinib in vitro. Conclusions: Neutralizing ISR hyperactivation could prevent or reverse ponatinib-induced cardiotoxicity. The findings that compromised ATP production potentiates GCN2-mediated ISR activation have broad implications across various cardiac diseases. Our results also highlight an unanticipated role of ponatinib in causing direct activation of a kinase target despite its role as an ATP-competitive kinase inhibitor.

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“…9 ISR activation by the OMA1-DELE1-HRI pathway is protective in several genetic mouse models of mitochondrial cardiomyopathy. 10–12 These studies demonstrate the protective role of the ISR in cardiac pathophysiology.…”

mentioning

confidence: 74%

Ponatinib-Induced Cardiomyocyte Toxicity: Dark Side of the Integrated Stress Response

Liang,

Moslehi,

Kitsis

2024

Circulation Research

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Mitochondrial Stress Induces an HRI-eIF2α Pathway Protective for Cardiomyopathy

Cited by 15 publications

References 5 publications

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity

Ponatinib-Induced Cardiomyocyte Toxicity: Dark Side of the Integrated Stress Response

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