title: Stimulatory effect of CSE-generated H2S on hepatic mitochondrial biogenesis and the underlying mechanisms.
abstract: We previously showed that hydrogen sulfide (H2S) upregulates peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in primary hepatocytes. PGC-1α is a crucial regulator of mitochondrial biogenesis, a process required to maintain cellular energy homeostasis. We investigated the regulation of hepatic mitochondrial biogenesis by cystathionine γ-lyase (CSE)-generated H2S under physiological conditions. Primary hepatocytes isolated from CSE knockout (KO) and wild-type (WT) mice were used in all experiments. Mitochondrial DNA (mtDNA) and mRNA levels were measured via real-time PCR. Protein S-sulfhydration was determined via a modified biotin switch assay. MitoTracker Green was used to quantify mitochondrial content and distribution. CSE-KO hepatocytes produced less mtDNA compared to WT hepatocytes. Mitochondrial content was reduced in CSE-KO hepatocytes compared to WT hepatocytes, which was restored with NaHS (an H2S donor) treatment. CSE-KO hepatocytes exhibited lower levels of mitochondrial transcription factors and the mitochondrial transcription coactivator, peroxisome proliferator-activated receptor-γ coactivator-related protein (PPRC) compared to WT hepatocytes. NaHS administration upregulated PPRC, yet downregulated PGC-1β protein level in mouse hepatocytes. Exogenous H2S induced the S-sulfhydration of PPRC, which was lower in untreated CSE-KO hepatocytes, but not that of PGC-1β. Finally, knockdown of either PGC-1α or PPRC significantly decreased NaHS-stimulated mitochondrial biogenesis in hepatocytes, where knockdown of both genes were required to abolish NaHS-induced mitochondrial biogenesis. Endogenous H2S-induced liver mitochondrial biogenesis is dependent upon PGC-1α and PPRC signaling in primary hepatocytes. This study may offer clues to the regulation of energy homeostasis under physiological conditions as well as mitochondrial dysregulation.
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Health Sciences, Lakehead University, ON, Canada; Thunder Bay Regional Research Institute, ON, Canada.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Untereiner
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Health Sciences, Lakehead University, ON, Canada; Thunder Bay Regional Research Institute, ON, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Biology, Laurentian University, ON, Canada.
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Biology, Laurentian University, ON, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Kinesiology, Lakehead University, ON, Canada.
authors.forename: YoungJun
authors.initials: Y
authors.lastname: Ju
authors.affiliation: The Cardiovascular and Metabolic Research Unit, Lakehead University, ON, Canada; Department of Health Sciences, Lakehead University, ON, Canada; Thunder Bay Regional Research Institute, ON, Canada. Electronic address: lwu@lakeheadu.ca.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology* / Q000648:ultrastructure; D006609:High Mobility Group Proteins / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008099:Liver / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D051265:NF-E2-Related Factor 1 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D051265:NF-E2-Related Factor 1; D051267:NF-E2-Related Factor 2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D006180:Proton-Translocating ATPases; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: H(2)S; Mitochondrial biogenesis; Mouse hepatocytes; PGC-1α; PGC-1β; PPRC