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Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

ABSTRACT: Glycosylation with O-linked ?-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit ? (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as A?-treated cells. Indeed, A? bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the A?-induced impairment in ATP production and ATPase activity. These results indicate that A?-mediated reduction of ATP synthase activity in AD pathology results from direct binding between A? and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A.

SUBMITTER: Cha MY

PROVIDER: S-EPMC5007609 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

Cha Moon-Yong MY Cho Hyun Jin HJ Kim Chaeyoung C Jung Yang Ouk YO Kang Min Jueng MJ Murray Melissa E ME Hong Hyun Seok HS Choi Young-Joo YJ Choi Heesun H Kim Dong Kyu DK Choi Hyunjung H Kim Jisoo J Dickson Dennis W DW Song Hyun Kyu HK Cho Jin Won JW Yi Eugene C EC Kim Jungsu J Jin Seok Min SM Mook-Jung Inhee I

Human molecular genetics 20150910 22

Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased i ...[more]

PMID: 26358770

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Project description:New findingsWhat is the central question of this study? Humans with obesity have lower ATP synthesis in muscle along with lower content of the β-subunit of the ATP synthase (β-F1-ATPase), the catalytic component of the ATP synthase. Does lower synthesis rate of β-F1-ATPase in muscle contribute to these responses in humans with obesity? What is the main finding and its importance? Humans with obesity have a lower synthesis rate of β-F1 -ATPase and ATP synthase specific activity in muscle. These findings indicate that reduced production of subunits forming the ATP synthase in muscle may contribute to impaired generation of ATP in obesity.AbstractThe content of the β-subunit of the ATP synthase (β-F1 -ATPase), which forms the catalytic site of the enzyme ATP synthase, is reduced in muscle of obese humans, along with a reduced capacity for ATP synthesis. We studied 18 young (37 ± 8 years) subjects of which nine were lean (BMI = 23 ± 2 kg m-2 ) and nine were obese (BMI = 34 ± 3 kg m-2 ) to determine the fractional synthesis rate (FSR) and gene expression of β-F1 -ATPase, as well as the specific activity of the ATP synthase. FSR of β-F1 -ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of β-F1 -ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle β-F1 -ATPase FSR (0.10 ± 0.05 vs. 0.06 ± 0.03% h-1 ; P < 0.05) and protein expression (P < 0.05), but not mRNA expression (P > 0.05). Across subjects, abundance of β-F1 -ATPase correlated with the FSR of β-F1 -ATPase (P < 0.05). The specific activity of muscle ATP synthase was lower in obese compared to lean subjects (0.035 ± 0.004 vs. 0.042 ± 0.007 arbitrary units; P < 0.05), but this difference was not significant after the activity of the ATP synthase was adjusted to the β-F1 -ATPase content (P > 0.05). Obesity impairs the synthesis of β-F1 -ATPase in muscle at the translational level, reducing the content of β-F1 -ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.

Dataset Information

Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

Publications

Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

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