title: SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK.
abstract: Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levelsin vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that lack of Sirt4 activates a retrograde signaling response from the mitochondria to the nucleus that includes AMPK, PGC1α, key regulators of β-oxidation such as Acetyl-CoA carboxylase, and components of the mitochondrial respiratory machinery. This study highlights the ability of Sirt4 to regulate ATP levels via ANT2 and a feedback loop involving AMPK.
authors.forename: Linh
authors.initials: L
authors.lastname: Ho
authors.forename: Allen Sam
authors.initials: AS
authors.lastname: Titus
authors.forename: Kushal Kr
authors.initials: KK
authors.lastname: Banerjee
authors.forename: Suji
authors.initials: S
authors.lastname: George
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.forename: Shaunak
authors.initials: S
authors.lastname: Deota
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
authors.forename: Philipp
authors.initials: P
authors.lastname: Gut
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Ullas
authors.initials: U
authors.lastname: Kolthur-Seetharam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D033742:Adenine Nucleotide Translocator 2 / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019069:Cell Respiration; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063269:Mitochondrial Turnover; D010084:Oxidation-Reduction; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism*
chemical_list: D033742:Adenine Nucleotide Translocator 2; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; C525357:SIRT4 protein, human; C514813:SIRT4 protein, mouse; D037761:Sirtuins