Reduced Levels of Mitochondrial Complex I Subunit NDUFB8 and Linked Complex I + III Oxidoreductase Activity in the TgCRND8 Mouse Model of Alzheimer's Disease

Francis, Beverly M.; Yang, Jimao; Song, Byung Jun; Gupta, Saurabh; Maj, Mary C.; Bazinet, Richard P.; Robinson, Brian H.; Mount, Howard T.J.

doi:10.3233/jad-131499

Cited by 24 publications

(16 citation statements)

References 41 publications

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“…As demonstrated in various neurodegenerative disorders, complex I seem to have an increased susceptibility to toxic protein species [26, 53, 70]. Since the observed mitochondrial pathology clearly preceded the clinical manifestation of muscle weakness in homozygous R349P desmin knock-in mice [16], we conclude that mutant desmin-induced mitochondrial dysfunction defines early disease stages, which significantly contribute to the progressive muscle damage in autosomal-recessive desminopathies with maintained expression of mutant desmin.…”

Section: Discussionsupporting

confidence: 52%

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

et al. 2016

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Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive. To address this issue for protein aggregate myopathies, we performed a comprehensive, multi-level analysis of mitochondrial pathology in skeletal muscles of human patients with mutations in the intermediate filament protein desmin and in muscles of hetero- and homozygous knock-in mice carrying the R349P desmin mutation. We demonstrate that the expression of mutant desmin causes disruption of the extrasarcomeric desmin cytoskeleton and extensive mitochondrial abnormalities regarding subcellular distribution, number and shape. At the molecular level, we uncovered changes in the abundancy and assembly of the respiratory chain complexes and supercomplexes. In addition, we revealed a marked reduction of mtDNA- and nuclear DNA-encoded mitochondrial proteins in parallel with large-scale deletions in mtDNA and reduced mtDNA copy numbers. Hence, our data demonstrate that the expression of mutant desmin causes multi-level damage of mitochondria already in early stages of desminopathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 52%

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

et al. 2016

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“…Quantification of ETC complexes demonstrated a marked reduction of Complex I subunit NDUFB8 (0.25 ± 0.06 of control) and Complex IV subunit MTCO2 (0.26 ± 0.04 of control) in the MELAS cells compared with the controls (Figure 1B, 1E ). Subunits NDUFB8 and MTCO2 are crucial for the assembly of the membrane arm of Complex I and catalytic core of Complex IV, respectively [ 11 , 12 ]. Deficiency of subunits NDUFB8 and MTCO2 resulted in reduced abundance, stability and activity of Complexes I and IV, respectively [ 11 , 12 ].…”

Section: Resultsmentioning

confidence: 99%

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease

Lin

Kao

et al. 2017

Oncotarget

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Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMP-activated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

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“…The process is supposed to be as follow: decreased mitochondrial sirt3 likely suppresses the activation of mitochondrial complex I subunits of ETC proteins, which further declines of NAD ? generation, increases ROS production consequently, and inhibits ATP generation [27][28][29]. In addition, decreased sirt3 might inhibit the regulatory factors of mitochondrial biogenesis, nuclear respiratory factor-1, transcription factor A, as well as peroxisome proliferator activated receptor c coactivator-1a, causing defect of mitochondrial biogenesis [30].…”

Section: Discussionmentioning

confidence: 98%

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

et al. 2015

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Emerging data suggests that mitochondrial dysfunction is prominently involved in Alzheimer disease (AD) progression. Sirtuin-3 (Sirt3) is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases that regulates a variety of mitochondrial functions and suppresses mitochondria-related physiology. Here, we determined sirt3 expression in a mouse model of AD. Spatial learning and memory were tested by Morris water maze in APP/PS1 double transgenic mice. The expression of sirt3 was assayed by real-time quantitative PCR and western blotting. Age-and gender-matched wild-type (WT) littermates were used as controls. Cortical sirt3 localization was assessed using immunohistochemistry. The expression of sirt3 mRNA was significantly lower in the cortex of APP/PS1 double transgenic mice than in WT littermates (0.83 ± 0.24 vs. 1.10 ± 0.21, P < 0.05). A comparable reduction was found in sirt3 protein levels using western blotting. The ratio of mean optical density (MOD) of total sirt3/β-actin in the cortex was 0.77 ± 0.11 in APP/PS1 double transgenic mice and 1.34 ± 0.17 in the WT littermates (P < 0.01). Immunohistochemistry showed the same change as western blotting. The ratio of MOD of integral optical density/total area in APP/PS1 and WT littermates was 0.58 ± 0.02 and 0.71 ± 0.05 (P < 0.01). These data show that sirt3 was depleted in APP/PS1 double transgenic mice. The results suggest that mitochondrial sirt3 might participate in the development of AD via mitochondrial dysfunction.

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Reduced Levels of Mitochondrial Complex I Subunit NDUFB8 and Linked Complex I + III Oxidoreductase Activity in the TgCRND8 Mouse Model of Alzheimer's Disease

Cited by 24 publications

References 41 publications

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease

Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer’s Disease

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