Functional study of the mitochondrial protein FAM162A in mitophagy during erythropoiesis
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Fecha
2023
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en
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Universidad Andrés Bello
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Licencia CC
Resumen
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.
Notas
Tesis (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.
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.
Palabras clave
Proteínas Mitocondriales, Mitofagia, Eritropoyesis