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Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
(2018) Elife 7:
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Beclin-1, Cell Respiration, Fibrosis, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Heart Diseases, Heart Ventricles, Humans, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proton-Translocating ATPases, Mutation, Myeloid Progenitor Cells, Myocardial Infarction, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Reactive Oxygen Species, Reproducibility of Results, Up-Regulation
Show Abstract · Added December 11, 2018
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
0 Communities
4 Members
0 Resources
26 MeSH Terms
SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress.
Vassilopoulos A, Pennington JD, Andresson T, Rees DM, Bosley AD, Fearnley IM, Ham A, Flynn CR, Hill S, Rose KL, Kim HS, Deng CX, Walker JE, Gius D
(2014) Antioxid Redox Signal 21: 551-64
MeSH Terms: ATP Synthetase Complexes, Acetylation, Adenosine Triphosphatases, Adenosine Triphosphate, Animals, Carrier Proteins, Cell Line, Enzyme Activation, Humans, Membrane Proteins, Mice, Mice, Knockout, Mitochondrial Proton-Translocating ATPases, Muscle, Skeletal, Physical Conditioning, Animal, Protein Binding, Sirtuin 3, Stress, Physiological
Show Abstract · Added October 5, 2015
AIMS - Adenosine triphosphate (ATP) synthase uses chemiosmotic energy across the inner mitochondrial membrane to convert adenosine diphosphate and orthophosphate into ATP, whereas genetic deletion of Sirt3 decreases mitochondrial ATP levels. Here, we investigate the mechanistic connection between SIRT3 and energy homeostasis.
RESULTS - By using both in vitro and in vivo experiments, we demonstrate that ATP synthase F1 proteins alpha, beta, gamma, and Oligomycin sensitivity-conferring protein (OSCP) contain SIRT3-specific reversible acetyl-lysines that are evolutionarily conserved and bind to SIRT3. OSCP was further investigated and lysine 139 is a nutrient-sensitive SIRT3-dependent deacetylation target. Site directed mutants demonstrate that OSCP(K139) directs, at least in part, mitochondrial ATP production and mice lacking Sirt3 exhibit decreased ATP muscle levels, increased ATP synthase protein acetylation, and an exercise-induced stress-deficient phenotype.
INNOVATION - This work connects the aging and nutrient response, via SIRT3 direction of the mitochondrial acetylome, to the regulation of mitochondrial energy homeostasis under nutrient-stress conditions by deacetylating ATP synthase proteins.
CONCLUSION - Our data suggest that acetylome signaling contributes to mitochondrial energy homeostasis by SIRT3-mediated deacetylation of ATP synthase proteins.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.
Pfeffer G, Blakely EL, Alston CL, Hassani A, Boggild M, Horvath R, Samuels DC, Taylor RW, Chinnery PF
(2012) J Neurol Neurosurg Psychiatry 83: 883-6
MeSH Terms: Adult, Age of Onset, Child, Preschool, Female, Genetic Testing, Humans, Male, Middle Aged, Mitochondrial Proton-Translocating ATPases, Mutation, Pedigree, Spinocerebellar Ataxias
Show Abstract · Added December 12, 2013
BACKGROUND - Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients.
METHODS - Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations.
RESULTS - Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal.
CONCLUSIONS - MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.
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1 Members
0 Resources
12 MeSH Terms
Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice.
Jones MK, Zhu E, Sarino EV, Padilla OR, Takahashi T, Shimizu T, Shirasawa T
(2011) Am J Physiol Gastrointest Liver Physiol 301: G537-46
MeSH Terms: Aconitate Hydratase, Animals, Apoptosis, Gastric Acid, Gastric Mucosa, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proton-Translocating ATPases, Oxidative Phosphorylation, Oxidative Stress, Parietal Cells, Gastric, Superoxide Dismutase, Superoxides
Show Abstract · Added August 27, 2013
Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P < 0.05) reduction in total gastric SOD activity and a 93% (P < 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P < 0.0001) and 44% (P < 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P < 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P < 0.0001) and 40% (P < 0.0005), respectively. There was a fourfold (P < 0.02) increase in gastric mucosal apoptosis and 41% (P < 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.
0 Communities
1 Members
0 Resources
14 MeSH Terms