Elorza G., ÁlvaroMatamoros, Andrea2024-06-042024-06-042023https://repositorio.unab.cl/handle/ria/57265Tesis (Doctora en Biomedicina)This research was funded by FONDECYT 1180983 “Targeting anemia through enhancing mitochondrial dynamics and mitophagy: Investigation of two novel mitochondrial proteins”, Millennium Institute on Immunology and Immunotherapy P09-016-F, and Research Initiation Fellowship UNAB 2022 DI-13-22/INI. Furthermore, I was initially funded by the doctoral fellowship from Universidad Andres Bello, Santiago, Chile; and the last 2 years, by the ANID Ph.D. Scholarships Chile / 2021 – 21212271.Erythropoiesis is the process to produce erythrocytes and its disruption or deficiency leads to anemia. Biomedical research has focused on erythropoiesis to identify novel therapeutic targets to treat anemia. Mitochondria have been linked to erythroid cell homeostasis and differentiation which go through constant mitophagy and biogenesis to keep functionality. The NIX protein, a BH3-only protein, has been described as the main player in the receptor-mediated mitophagy, although the Pink/Parkin canonical pathway has also been observed. However, in spite of the inhibition of those mitophagy pathways, mitophagy still occurs, suggesting there are other mechanisms involved. In this research, it was proposed that apoptotic mitochondrial protein FAM162A is a novel participant in mitophagy, needed for proper erythropoiesis. This is based on its similitude with other mitophagy proteins such as NIX, its expression pattern in erythropoiesis, and the presence of a putative LIR domain. Results showed that FAM162A knockdown impairs the autophagy flux and causes mitochondrial deficiency accumulation in HEK293T and COS7 cells. In contrast, FAM162A overexpression increases autophagy flux and improves mitochondrial turnover in stress conditions, implying that it plays a protective role in mitochondrial function. Furthermore, it was observed that FAM162A protein levels increase during differentiation in the erythroleukemia K562 cell line and human hematopoietic CD34+ stem cells. In erythropoiesis, FAM162A downregulation decreased the mitophagy flux, delayed differentiation and cell proliferation, inhibited heme biosynthesis, and disrupted erythropoiesis. Therefore, FAM162A is reported to be a novel mitochondrial protein participating in mitophagy. The mitophagy mechanism which FAM162A is involved in, is not known yet. However, it is discussed that FAM162A participates in the VDAC-TSPO-PINK/Parkin axis as a mechanism for mitophagy induction. The involvement of FAM162A in mitophagy means a great contribution to the mitochondrial field and will promote the discovery and development of novel biological or pharmacological compounds to treat mitophagy-related diseases.enProteínas MitocondrialesMitofagiaEritropoyesisTesis