2. Academic Validation
  3. Cardiomyocyte-specific Tbk1 deletion aggravated chronic doxorubicin cardiotoxicity via inhibition of mitophagy

Cardiomyocyte-specific Tbk1 deletion aggravated chronic doxorubicin cardiotoxicity via inhibition of mitophagy

  • Free Radic Biol Med. 2024 Jun 18:222:244-258. doi: 10.1016/j.freeradbiomed.2024.06.009.
Wenjun Yu 1,  Dawei Deng 2,  Yang Li 2,  Kehan Ding 2,  Qiaofeng Qian 2,  Hongjie Shi 2,  Qiujie Luo 2,  Jie Cai 3,  Jinping Liu 4
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, PR China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, PR China. Electronic address: yuwj0522@163.com.
  • 2 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, PR China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, PR China.
  • 3 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, PR China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, PR China. Electronic address: cjdoctor@163.com.
  • 4 Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, PR China; Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, PR China. Electronic address: liujinping@znhospital.cn.
PMID: 38901499 DOI: 10.1016/j.freeradbiomed.2024.06.009
Abstract

Doxorubicin (Dox) use is limited by Dox-induced cardiotoxicity. TANK-blinding kinase 1 (TBK1) is an important kinase involved in the regulation of Mitophagy, but the role of TBK1 in cardiomyocytes in chronic Dox-induced cardiomyopathy remains unclear. Cardiomyocyte-specific TBK1 knockout (TBK1CKO) mice received Dox (6 mg/kg, injected intraperitoneally) once a week for 4 times, and cardiac assessment was performed 4 weeks after the final Dox injection. Adenoviruses encoding TBK1 or containing shRNA targeting TBK1, or a TBK1 phosphorylation inhibitor were used for overexpression or knockdown of TBK1, or inhibit phosphorylation of TBK1 in isolated primary cardiomyocytes. Our results revealed that moderate Dox challenge decreased TBK1 phosphorylation (with no effect on TBK1 protein levels), resulting in compromised myocardial function, obvious mortality and overt interstitial fibrosis, and the effects were accentuated by TBK1 deletion. Dox provoked mitochondrial membrane potential collapse and oxidative stress, the effects of which were exacerbated and mitigated by TBK1 knockdown, specific inhibition of phosphorylation and overexpression, respectively. However, TBK1 （Ser172A） overexpression did not alleviate these effects. Further scrutiny revealed that TBK1 exerted protective effects on mitochondria via SQSTM1/P62-mediated Mitophagy. TBK1 overexpression mediated cardioprotective effects on Dox-induced cardiotoxicity were cancelled off by Sqstm1/p62 knockdown. Moreover, TBK1-mitophagy-mitochondria cascade was confirmed in heart tissues from dilated cardiomyopathy patients. Taken together, our findings denoted a pivotal role of TBK1 in Dox-induced mitochondrial injury and cardiotoxicity possibly through its phosphorylation and SQSTM1/P62-mediated Mitophagy.

Keywords

Doxorubicin cardiotoxicity; Mitochondria; Mitophagy; TBK1.

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