An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna

Dumesic, Phillip A.; Egan, Daniel F.; Gut, Philipp; Tran, Mei; Parisi, Alice; Chatterjee, Nirmalya; Jedrychowski, Mark P.; Paschini, Margherita; Kazak, Lawrence; Wilensky, Sarah; Dou, Florence Y.; Bogoslavski, Dina; Cartier, Jeffrey A.; Perrimon, Norbert; Kajimura, Shingo; Parikh, Samir M.; Spiegelman, Bruce M.

doi:10.1016/j.cmet.2019.04.013

Cited by 46 publications

(42 citation statements)

References 59 publications

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“…Conversely, mice with tubule-specific overexpression of PGC1α were protected against all three models of AKI 47,49,50 . The PPARGC1A locus, which encodes PGC1α, contains an evolutionarily conserved upstream open reading frame (uORF) in the 5′ untranslated region 51 . Such uORFs reduce protein expression by suppressing translation 52 .…”

Section: Nadpmentioning

confidence: 99%

NAD+ homeostasis in renal health and disease

2019

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Section: Nadpmentioning

confidence: 99%

NAD+ homeostasis in renal health and disease

2019

Self Cite

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“…For example, translation of small open reading frames in the 5 0 UTR-called upstream (u)ORFs-often decreases translation efficiency of the canonical ORF (Mueller & Hinnebusch, 1986;Vattem & Wek, 2004;Brar et al, 2012;von Arnim et al, 2014;Wethmar et al, 2014;Chew et al, 2016;Johnstone et al, 2016). Consistent with uORF translation serving important regulatory roles, uORFs are pervasive from yeast to human and their presence is conserved between orthologous genes despite having little similarity at the level of amino acid sequence (Chew et al, 2016;Johnstone et al, 2016;Dumesic et al, 2019). For example, fundamental developmental genes such as POU5F3 (Oct4), Nanog, and Smad7 encode multiple uORFs from zebrafish to human but the amino acid identity encoded by the uORF is not conserved (Johnstone et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Translation of small downstream ORFs enhances translation of canonical main open reading frames

Wright

Gogol

et al. 2020

The EMBO Journal

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In addition to canonical open reading frames (ORFs), thousands of translated small ORFs (containing less than 100 codons) have been identified in untranslated mRNA regions (UTRs) across eukaryotes. Small ORFs in 5′ UTRs (upstream (u)ORFs) often repress translation of the canonical ORF within the same mRNA. However, the function of translated small ORFs in the 3′ UTRs (downstream (d)ORFs) is unknown. Contrary to uORFs, we find that translation of dORFs enhances translation of their corresponding canonical ORFs. This translation stimulatory effect of dORFs depends on the number of dORFs, but not the length or peptide they encode. We propose that dORFs represent a new, strong, and universal translation regulatory mechanism in vertebrates.

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“…This enabled the symbiotic acquisition of mitochondria and the rise in complexity of metazoa over 700 million years ago, and the evolution of metabolic regulators such as hypoxia-inducible factor-1 (HIF1), peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1), retinoic acid receptor (RAR), and autophagy. 69,81,134,135 DNA methyltransferases (Dnmt) have regulated organ differentiation in response to nutritional energy signals for over 700 million years. 136 This is evidenced by silencing the expression of Dnmt3 in newly hatched honeybee larvae, which produces a royal jelly-like effect on larval development, with adults emerging as queens with fully developed ovaries.…”

Section: Slowed Somatic Growthmentioning

confidence: 99%

Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD

Chevalier

2020

Kidney360

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There is greater than tenfold variation in nephron number of the human kidney at birth. Although low nephron number is a recognized risk factor for CKD, its determinants are poorly understood. Evolutionary medicine represents a new discipline that seeks evolutionary explanations for disease, broadening perspectives on research and public health initiatives. Evolution of the kidney, an organ rich in mitochondria, has been driven by natural selection for reproductive fitness constrained by energy availability. Over the past 2 million years, rapid growth of an energy-demanding brain in Homo sapiens enabled hominid adaptation to environmental extremes through selection for mutations in mitochondrial and nuclear DNA epigenetically regulated by allocation of energy to developing organs. Maternal undernutrition or hypoxia results in intrauterine growth restriction or preterm birth, resulting in low birth weight and low nephron number. Regulated through placental transfer, environmental oxygen and nutrients signal nephron progenitor cells to reprogram metabolism from glycolysis to oxidative phosphorylation. These processes are modulated by counterbalancing anabolic and catabolic metabolic pathways that evolved from prokaryote homologs and by hypoxia-driven and autophagy pathways that evolved in eukaryotes. Regulation of nephron differentiation by histone modifications and DNA methyltransferases provide epigenetic control of nephron number in response to energy available to the fetus. Developmental plasticity of nephrogenesis represents an evolved life history strategy that prioritizes energy to early brain growth with adequate kidney function through reproductive years, the trade-off being increasing prevalence of CKD delayed until later adulthood. The research implications of this evolutionary analysis are to identify regulatory pathways of energy allocation directing nephrogenesis while accounting for the different life history strategies of animal models such as the mouse. The clinical implications are to optimize nutrition and minimize hypoxic/toxic stressors in childbearing women and children in early postnatal development.

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An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna

Abstract: Highlights d An upstream open reading frame represses translation of the PPARGC1A mRNA d uORF function is a conserved feature of human, fish, and fly PPARGC1A 5 0 UTRs d Atlantic bluefin tuna PPARGC1A 5 0 UTR lacks a uORF and supports elevated translation

Cited by 46 publications

References 59 publications

NAD+ homeostasis in renal health and disease

NAD+ homeostasis in renal health and disease

Translation of small downstream ORFs enhances translation of canonical main open reading frames

Bioenergetic Evolution Explains Prevalence of Low Nephron Number at Birth: Risk Factor for CKD

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