Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation

Xin Liu, Yuannyu Zhang, Min Ni, Hui Cao, Robert A.J. Signer, Dan Li, Mushan Li, Zhimin Gu, Zeping Hu, Kathryn E. Dickerson, Samuel E. Weinberg, Navdeep S. Chandel, Ralph J. Deberardinis, Feng Zhou, Zhen Shao, Jian Xu

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing.

Original languageEnglish (US)
Pages (from-to)626-638
Number of pages13
JournalNature cell biology
Volume19
Issue number6
DOIs
StatePublished - May 31 2017

ASJC Scopus subject areas

  • Cell Biology

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