Heart failure in patients is associated with downregulation of mitochondrial quality control genes

T Svagusa; S Sikiric; M Milavic; A Sepac; S Seiwerth; D Milicic; H Gasparovic; B Biocina; I Rudez; Z Sutlic; S Manola; J Varvodic; M Udovicic; M Urlic; S Ivankovic; S Plestina; F Paic; A Kulic; P Bakovic; F Sedlic

doi:10.1111/eci.14054

Heart failure in patients is associated with downregulation of mitochondrial quality control genes

Eur J Clin Invest. 2023 Nov;53(11):e14054. doi: 10.1111/eci.14054. Epub 2023 Jul 4.

Authors

T Svagusa¹, S Sikiric², M Milavic², A Sepac^{2

3}, S Seiwerth^{2

3}, D Milicic^{4

5}, H Gasparovic^{6

7}, B Biocina^{6

7}, I Rudez^{6

8}, Z Sutlic^{6

8}, S Manola¹, J Varvodic⁸, M Udovicic^{1

4}, M Urlic⁷, S Ivankovic⁹, S Plestina^{10

11}, F Paic¹², A Kulic¹¹, P Bakovic¹⁰, F Sedlic¹⁰

Affiliations

¹ Department of Cardiovascular Diseases, Dubrava Clinical Hospital, Zagreb, Croatia.
² Department of Pathology, University of Zagreb School of Medicine, Zagreb, Croatia.
³ Department of Pathology and Cytology, University Hospital Center Zagreb, Zagreb, Croatia.
⁴ Department of Internal Medicine, University of Zagreb School of Medicine, Zagreb, Croatia.
⁵ Department of Cardiovascular Diseases, University Hospital Center Zagreb, Zagreb, Croatia.
⁶ Department of Surgery, University of Zagreb School of Medicine, Zagreb, Croatia.
⁷ Department of Cardiac Surgery, University Hospital Center Zagreb, Zagreb, Croatia.
⁸ Department of Cardiac and Transplant Surgery, Dubrava Clinical Hospital, Zagreb, Croatia.
⁹ Department of Cardiac Surgery, University Hospital Center Split, Split, Croatia.
¹⁰ Department of Pathophysiology, University of Zagreb School of Medicine, Zagreb, Croatia.
¹¹ Department of Oncology, University Hospital Centre Zagreb, Zagreb, Croatia.
¹² Department of Medical Biology, University of Zagreb School of Medicine, Zagreb, Croatia.

PMID: 37403271
DOI: 10.1111/eci.14054

Abstract

Background: Mitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure.

Methods: Myocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real-time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion-fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry.

Results: The following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT-ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM.

Conclusions: Heart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion-fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.

Keywords: MQC; TIM; UPRmt; heart; mitochondria; mitophagy.

Abstract

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