Macrod1, also known as Leukemia related protein 16 (LRP16), is an ADP-ribosylhydrolase 1 highly enriched in mitochondria [1,3,5]. It participates in the hydrolysis of protein mono-ADP-ribosylation, and is involved in pathways such as the PARP1-NAD+-SIRT3 axis [1,2]. Dysregulation of Macrod1 has been associated with the pathogenesis of several diseases including cardiovascular diseases and cancer [1,3,4]. Genetic models like knockout mice are valuable for studying its functions.

In a mouse model of diabetic cardiomyopathy (DCM), Macrod1 expression was downregulated in cardiac tissue. Knockout of Macrod1 in DCM mice worsened glycemic control, aggravated cardiac remodeling, mitochondrial dysfunction, NAD+ consumption and oxidative stress. In contrast, cardiac-specific overexpression of Macrod1 partially reversed these pathological processes. In vitro, overexpression of Macrod1 in palmitic acid-treated neonatal rat cardiomyocytes inhibited PARP1 expression, restored NAD+ levels, and activated SIRT3 to resist oxidative stress [1].

In summary, Macrod1 plays a crucial role in maintaining mitochondrial function and regulating oxidative stress, especially in the context of DCM. The use of Macrod1 knockout mouse models has provided significant insights into its role in this disease, highlighting its potential as a novel target for DCM treatment [1].

References:

1. Liu, Yu-Ting, Qiu, Hong-Liang, Xia, Hong-Xia, Che, Yan, Tang, Qi-Zhu. 2024. Macrod1 suppresses diabetic cardiomyopathy via regulating PARP1-NAD+-SIRT3 pathway. In Acta pharmacologica Sinica, 45, 1175-1188. doi:10.1038/s41401-024-01247-2. https://pubmed.ncbi.nlm.nih.gov/38459256/

2. Yang, Xiaoyun, Ma, Yinliang, Li, Yimiao, Yu, Xiaochun, Liu, Xiuhua. 2020. Molecular basis for the MacroD1-mediated hydrolysis of ADP-ribosylation. In DNA repair, 94, 102899. doi:10.1016/j.dnarep.2020.102899. https://pubmed.ncbi.nlm.nih.gov/32683309/

3. Agnew, Thomas, Munnur, Deeksha, Crawford, Kerryanne, Mikoč, Andreja, Ahel, Ivan. 2018. MacroD1 Is a Promiscuous ADP-Ribosyl Hydrolase Localized to Mitochondria. In Frontiers in microbiology, 9, 20. doi:10.3389/fmicb.2018.00020. https://pubmed.ncbi.nlm.nih.gov/29410655/

4. Feijs, Karla L H, Cooper, Christopher D O, Žaja, Roko. 2020. The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis. In Cancers, 12, . doi:10.3390/cancers12030604. https://pubmed.ncbi.nlm.nih.gov/32151005/

5. Žaja, R, Aydin, G, Lippok, B E, Lüscher, B, Feijs, K L H. 2020. Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome. In Scientific reports, 10, 8286. doi:10.1038/s41598-020-64623-y. https://pubmed.ncbi.nlm.nih.gov/32427867/