Poster abstracts
Poster number 76 submitted by Jiangbin Wu
FAM210A Deficiency Causes Dilated Cardiomyopathy through Persistent Activation of Integrated Stress Response
Jiangbin Wu (Aab Cardiovascular Research Institute, University of Rochester Medical Center), Kadiam C. Venkata Subbaiah (Aab Cardiovascular Research Institute, University of Rochester Medical Center), Omar Hedaya (Aab Cardiovascular Research Institute & Department of Biochemistry and Biophysics. University of Rochester Medical Center), Si Chen (Aab Cardiovascular Research Institute & Department of Pharmacology and Physiology. University of Rochester Medical Center), Chen Yan (Aab Cardiovascular Research Institute & Department of Pharmacology and Physiology. University of Rochester Medical Center), Peng Yao (Aab Cardiovascular Research Institute & Department of Biochemistry and Biophysics. University of Rochester Medical Center)
Abstract:
Heart is one of the most mitochondria enriched organ in mammals. Disturbed cardiac mitochondrial homeostasis causes mitochondrial cardiomyopathy. Integrated stress response (ISR), a major pathway downstream of multiple mitochondrial stresses, regulates translation initiation and reprograms global cellular translatome. FAM210A (family with sequence similarity 210 member A) is a mitochondria localized protein and essential for embryonic development. Prior research indicates that FAM210A is most highly expressed in the heart and FAM210A is a critical determinant of skeletal muscle function. However, the function of FAM210A in the heart is still unexplored. Here we discover that FAM210A is critical for maintaining cardiac mitochondrial function and homeostasis. Cardiomyocyte (CM) specific knockout (KO) of Fam210a in adult mice leads to progressive heart failure with enlarged left ventricle chamber, and ultimately causes mortality at ~70 days after Fam210a KO. The FAM210A deficient CMs exhibit severe myofilament disarray at ~9 weeks post Fam210a KO at late stage. Furthermore, Fam210a KO results in a remarkably elevated mitochondrial ROS production, dramatically compromised mitochondrial membrane potential, and reduced expression of mitochondrial electron transport chain (ETC) complex genes. As a result, the mitochondrial respiratory activity is significantly reduced and the mitochondrial cristae are disrupted in Fam210a KO CMs. However, at early stage of ~5 weeks post tamoxifen induced Fam210a KO, we only observed increased mitochondrial ROS production, disturbed mitochondrial membrane potential, and reduced respiratory activity while the heart function keeps normal. Transcriptomic and proteomic analyses from Fam210a KO hearts indicate that majority of genes upregulated at both early and late stages are downstream targets of ATF4 transcription factor. Phosphorylation of eIF2&alpha is greatly enhanced at the early stage, suggesting that FAM210A deficiency caused mitochondrial dysfunctions and chronic ISR activation and translational reprogramming, ultimately leading to heart failure. Altogether, we discover a novel function of FAM210A in maintaining the cardiac mitochondrial function, and deficiency of FAM210A causes persistent activation of ISR and leads to heart failure.
References:
1. Tahmasebi, S., et al. Nat Rev Mol Cell Biol 19, 791-807, doi:10.1038/s41580-018-0034-x (2018).
2. Costa-Mattioli, M. & Walter, P. Science 368, doi:10.1126/science.aat5314 (2020).
3. Rozman, J. et al. Nature communications 9, 288, doi:10.1038/s41467-017-01995-2 (2018).
4. Dickinson, M. E. et al. Nature 537, 508-514, doi:10.1038/nature19356 (2016).
5. Estrada, K. et al. Nat Genet 44, 491-501, doi:10.1038/ng.2249 (2012).
6 Tanaka, K. I. et al. Proc Natl Acad Sci U S A 115, E3759-E3768, doi:10.1073/pnas.1719089115 (2018).
Keywords: FAM210A, mitochondrial dysfunction, integrated stress response