TY - JOUR
T1 - Mitochondrial superoxide targets energy metabolism to modulate epigenetic regulation of NRF2-mediated transcription
AU - Dhar, Sanjit K.
AU - Scott, Timothy
AU - Wang, Chi
AU - Fan, Teresa W.M.
AU - St Clair, Daret K.
N1 - Publisher Copyright:
© 2021
PY - 2022/2/1
Y1 - 2022/2/1
N2 - Mitochondria are central to the metabolic circuitry that generates superoxide radicals/anions (O2•-) as a by-product of oxygen metabolism. By regulating superoxide levels, manganese superoxide dismutase plays important roles in numerous biochemical and molecular events essential for the survival of aerobic life. In this study, we used MitoParaquat (mPQ) to generate mitochondria-specific O2•- and stable isotope-resolved metabolomics tracing in primary human epidermal keratinocytes to investigate how O2•- generated in mitochondria regulates gene expression. The results reveal that isocitrate is blocked from conversion to α-ketoglutarate and that acetyl-coenzyme A (CoA) accumulates, which is consistent with a reduction in oxygen consumption rate and inactivation of isocitrate dehydrogenase (IDH) activity. Since acetyl-CoA is linked to histone acetylation and gene regulation, we determined the effect of mPQ on histone acetylation. The results demonstrate an increase in histone H3 acetylation at lysines 9 and 14. Suppression of IDH increased histone acetylation, providing a direct link between metabolism and epigenetic alterations. The activity of histone acetyltransferase p300 increased after mPQ treatment, which is consistent with histone acetylation. Importantly, mPQ selectively increased the nuclear levels and activity of the oxidative stress-sensitive nuclear factor erythroid 2-related factor 2. Together, the results establish a new paradigm that recognizes O2•- as an initiator of metabolic reprogramming that activates epigenetic regulation of gene transcription in response to mitochondrial dysfunction.
AB - Mitochondria are central to the metabolic circuitry that generates superoxide radicals/anions (O2•-) as a by-product of oxygen metabolism. By regulating superoxide levels, manganese superoxide dismutase plays important roles in numerous biochemical and molecular events essential for the survival of aerobic life. In this study, we used MitoParaquat (mPQ) to generate mitochondria-specific O2•- and stable isotope-resolved metabolomics tracing in primary human epidermal keratinocytes to investigate how O2•- generated in mitochondria regulates gene expression. The results reveal that isocitrate is blocked from conversion to α-ketoglutarate and that acetyl-coenzyme A (CoA) accumulates, which is consistent with a reduction in oxygen consumption rate and inactivation of isocitrate dehydrogenase (IDH) activity. Since acetyl-CoA is linked to histone acetylation and gene regulation, we determined the effect of mPQ on histone acetylation. The results demonstrate an increase in histone H3 acetylation at lysines 9 and 14. Suppression of IDH increased histone acetylation, providing a direct link between metabolism and epigenetic alterations. The activity of histone acetyltransferase p300 increased after mPQ treatment, which is consistent with histone acetylation. Importantly, mPQ selectively increased the nuclear levels and activity of the oxidative stress-sensitive nuclear factor erythroid 2-related factor 2. Together, the results establish a new paradigm that recognizes O2•- as an initiator of metabolic reprogramming that activates epigenetic regulation of gene transcription in response to mitochondrial dysfunction.
KW - Epigenetics
KW - Metabolism
KW - Mitochondria
KW - Superoxide
KW - TCA cycle
KW - Transcription
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U2 - 10.1016/j.freeradbiomed.2021.12.309
DO - 10.1016/j.freeradbiomed.2021.12.309
M3 - Article
C2 - 34968705
AN - SCOPUS:85122178910
SN - 0891-5849
VL - 179
SP - 181
EP - 189
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -