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2016 ; 291
(24
): 12575-12585
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p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria
#MMPMID27059956
Tomilov A
; Tomilova N
; Shan Y
; Hagopian K
; Bettaieb A
; Kim K
; Pelicci PG
; Haj F
; Ramsey J
; Cortopassi G
J Biol Chem
2016[Jun]; 291
(24
): 12575-12585
PMID27059956
show ga
Although the p46Shc isoform has been known to be mitochondrially localized for 11
years, its function in mitochondria has been a mystery. We confirmed p46Shc to be
mitochondrially localized and showed that the major mitochondrial partner of
p46Shc is the lipid oxidation enzyme 3-ketoacylCoA thiolase ACAA2, to which
p46Shc binds directly and with a strong affinity. Increasing p46Shc expression
inhibits, and decreasing p46Shc stimulates enzymatic activity of thiolase in
vitro Thus, we suggest p46Shc to be a negative mitochondrial thiolase activity
regulator, and reduction of p46Shc expression activates thiolase. This is the
first demonstration of a protein that directly binds and controls thiolase
activity. Thiolase was thought previously only to be regulated by metabolite
balance and steady-state flux control. Thiolase is the last enzyme of the
mitochondrial fatty acid beta-oxidation spiral, and thus is important for energy
metabolism. Mice with reduction of p46Shc are lean, resist obesity, have higher
lipid oxidation capacity, and increased thiolase activity. The thiolase-p46Shc
connection shown here in vitro and in organello may be an important underlying
mechanism explaining the metabolic phenotype of Shc-depleted mice in vivo.
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