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Mitochondrial dysfunction has been implicated in GSD\u2010Ia but the underlying mechanism and its contribution to HCA\/HCC development remain unclear. We have shown that hepatic G6Pase\u2010\u03b1 deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD\u2010Ia. SIRT1 is a NAD<jats:sup>+<\/jats:sup>\u2010dependent deacetylase that can deacetylate and activate peroxisome proliferator\u2010activated receptor\u2010\u03b3 coactivator 1\u03b1 (PGC\u20101\u03b1), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase\u2010\u03b1\u2010deficient livers impairs PGC\u20101\u03b1 activity, leading to mitochondrial dysfunction. Here we show that the G6Pase\u2010\u03b1\u2010deficient livers display defective PGC\u20101\u03b1 signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC\u20101\u03b1 activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase\u2010\u03b1 expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase\u2010\u03b1 expression also restores PGC\u20101\u03b1 activity and mitochondrial function. Finally, we show that HCA\/HCC lesions found in G6Pase\u2010\u03b1\u2010deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1\/PGC\u20101\u03b1 signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA\/HCC development in GSD\u2010Ia.<\/jats:p>","DOI":"10.1007\/s10545-018-0192-1","type":"journal-article","created":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T13:44:23Z","timestamp":1525787063000},"page":"997-1006","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia"],"prefix":"10.1002","volume":"41","author":[{"given":"Jun\u2010Ho","family":"Cho","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Building 10, Room 8N240C, NIH, 10 Center Drive Bethesda MD 20892\u20101830 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goo\u2010Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Building 10, Room 8N240C, NIH, 10 Center Drive Bethesda MD 20892\u20101830 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian C.","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Building 10, Room 8N240C, NIH, 10 Center Drive Bethesda MD 20892\u20101830 USA"},{"name":"Foundation Fighting Blindness Columbia MD 21046 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-6516","authenticated-orcid":false,"given":"Janice Y.","family":"Chou","sequence":"additional","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Building 10, Room 8N240C, NIH, 10 Center Drive Bethesda MD 20892\u20101830 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