Mice with Mitochondrial Complex I Deficiency Develop a Fatal Encephalomyopathy

Kruse, Shane E.; Watt, W. C.; Marcinek, David J.; Kapur, Raj P.; Schenkman, Kenneth A.; Palmiter, Richard D.

doi:10.1016/j.cmet.2008.02.004

Cited by 346 publications

(457 citation statements)

References 44 publications

Supporting

Mentioning

427

Contrasting

Order By: Relevance

“…Rates were reported after substracting non‐mitochondrial oxygen consumption as previously described (Kruse et al ., 2008). Briefly, leak respiration was determined in the presence of 10 m m glutamate, 5 m m pyruvate, and 2 m m malate in the absence of adenylates.…”

Section: Methodsmentioning

confidence: 99%

“…Mitochondrial dysfunction can also reach across point of origin to the entire organism affecting distal tissues. Inhibition of over half the maximal activity of complex I does not necessarily result in a commensurate decrease of in vivo basal ATP synthase activity (Kruse et al ., 2008). However, changes in complex I stoichiometry can affect the efficiency of electron transfer and result in oxidative stress (Miwa et al ., 2014) and slight alterations of the redox status of electron donors such as NAD/NADH can have genomewide effects (Imai & Guarente, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

et al. 2015

Self Cite

View full text Add to dashboard Cite

SummaryChanges in mitochondrial function with age vary between different muscle types, and mechanisms underlying this variation remain poorly defined. We examined whether the rate of mitochondrial protein turnover contributes to this variation. Using heavy label proteomics, we measured mitochondrial protein turnover and abundance in slow‐twitch soleus (SOL) and fast‐twitch extensor digitorum longus (EDL) from young and aged mice. We found that mitochondrial proteins were longer lived in EDL than SOL at both ages. Proteomic analyses revealed that age‐induced changes in protein abundance differed between EDL and SOL with the largest change being increased mitochondrial respiratory protein content in EDL. To determine how altered mitochondrial proteomics affect function, we measured respiratory capacity in permeabilized SOL and EDL. The increased mitochondrial protein content in aged EDL resulted in reduced complex I respiratory efficiency in addition to increased complex I‐derived H2O2 production. In contrast, SOL maintained mitochondrial quality, but demonstrated reduced respiratory capacity with age. Thus, the decline in mitochondrial quality with age in EDL was associated with slower protein turnover throughout life that may contribute to the greater decline in mitochondrial dysfunction in this muscle. Furthermore, mitochondrial‐targeted catalase protected respiratory function with age suggesting a causal role of oxidative stress. Our data clearly indicate divergent effects of age between different skeletal muscles on mitochondrial protein homeostasis and function with the greatest differences related to complex I. These results show the importance of tissue‐specific changes in the interaction between dysregulation of respiratory protein expression, oxidative stress, and mitochondrial function with age.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Patients with NDUFS4 mutations typically have two null-type mutations and develop the neurodegenerative condition, Leigh syndrome (15). Ndufs4 knockout mice develop encephalomyopathy and die within 7 wk (16). A brain-specific Ndufs4 knockout showed a nearly identical phenotype to the systemic knockout with death by 7 wk (17).…”

mentioning

confidence: 99%

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Pepe

Grubb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6 gt/gt mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6 gt/gt mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6 gt/gt mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6 gt/gt hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6 gt/gt mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6 gt/gt isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches. mouse model | mitochondrial diseases M itochondria generate the majority of energy required for cellular function and survival. Defects in mitochondrial oxidative phosphorylation (OXPHOS) cause a wide range of diseases, collectively affecting ∼1/5,000 births (1). OXPHOS dysfunction was first identified in neuromuscular disorders but symptoms can potentially affect any organ, with any age of onset and any mode of inheritance (2). The heart, being highly energy dependent, is particularly vulnerable to OXPHOS defects, with cardiac involvement recognized in about a third of children and up to 80% of adults with OXPHOS disorders (3, 4). Complex I (CI) deficiency is the most common OXPHOS disorder and has a wide range of clinical presentations, including neurodegeneration, muscle weakness, cardiac failure, liver failure, and early death, often in childhood (5, 6). As identified by Cochrane review, "there is currently no clear evidence supporting the use of any intervention in OXPHOS disorders" (7). Thus, there is an urgent need for suitable animal models to study pathogenic mechanisms and novel therapeutic approaches. Such models can also shed light on the wide range of common, complex diseases to which mitochondrial dysfunction contributes (8).Despite the high prevalence of OXPHOS disorders, relatively few genetic models have been...

show abstract

“…Likewise, mice with a homozygous deletion of an ETC complex I subunit (Ndufs4 knockout mice) also show reduced longevity. Both of these mutant mouse models are very short‐lived and have severe respiratory and metabolic phenotypes (Kruse et al., 2008; Wang, Oxer & Hekimi, 2015). One explanation for the seemingly contradictory effects of ETC mutation and longevity is a threshold effect in which compromised mitochondrial function alters cellular function only once a critical deficiency in ATP production in reached.…”

Section: Discussionmentioning

confidence: 99%

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

et al. 2018

View full text Add to dashboard Cite

SummaryLoss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 −/− mice. The lack of deleterious phenotypes in Surf1 −/− mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 −/− vs. Surf1 +/+ mice despite substantial decreases in COX activity (22%–87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 +/+ and Surf1 −/− mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 +/+ and Surf1 −/− mice. Gene expression was differentially regulated in a tissue‐specific manner. Many proteins and metabolites are downregulated in Surf1 −/− adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1 −/− mice. Finally, mitochondrial unfolded protein response (UPRmt)‐associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1 −/− mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan.

show abstract

Mice with Mitochondrial Complex I Deficiency Develop a Fatal Encephalomyopathy

Cited by 346 publications

References 44 publications

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

Age modifies respiratory complex I and protein homeostasis in a muscle type‐specific manner

Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy

Lifelong reduction in complex IV induces tissue‐specific metabolic effects but does not reduce lifespan or healthspan in mice

Contact Info

Product

Resources

About