Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism

Stauch, Kelly L.; Purnell, Phillip R.; Villeneuve, Lance M.; Fox, Howard S.

doi:10.1002/pmic.201400277

Cited by 43 publications

(63 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tissue was chopped and homogenized using a Dounce homogenizer. Synaptic mitochondria were isolated using a synaptosomal mitochondria preparation as previously performed [30–32]. Mitochondria for mass spectrometry were lysed in 4% sodium dodecyl sulfate (SDS), and protein concentration was quantified using a using a Pierce 660 assay with bovine serum albumin standards (Thermo Fisher Scientific, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

et al. 2016

Self Cite

View full text Add to dashboard Cite

With the advent of the combination antiretroviral therapy era (cART), the development of AIDS has been largely limited in the United States. Unfortunately, despite the development of efficacious treatments, HIV-1 associated neurocognitive disorders (HAND) can still develop and as many HIV-1 positive individuals age, the prevalence of HAND is likely to rise because HAND manifests in the brain with very low levels of virus. However, the mechanism producing this viral disorder is still debated. Interestingly, HIV-1 infection exposes neurons to proteins including Tat, Nef, Vpr which can drastically alter mitochondrial properties. Mitochondrial dysfunction has been posited to be a cornerstone of the development of numerous neurodegenerative diseases. Therefore, we investigated mitochondria in an animal model of HAND. Using an HIV-1 transgenic rat model expressing 7 of the 9 HIV-1 viral proteins, mitochondrial functional and proteomic analysis were performed on a subset of mitochondria that are particularly sensitive to cellular changes, the neuronal synaptic mitochondria. Quantitative mass spectroscopic studies followed by statistical analysis revealed extensive proteome alteration in this model paralleling mitochondrial abnormalities identified in HIV-1 animal models and HIV-1 infected humans. Novel mitochondrial protein changes were discovered in the electron transport chain (ETC), the glycolytic pathways, mitochondrial trafficking proteins, and proteins involved in various energy pathways, and these findings correlated well with the function of the mitochondria as assessed by a mitochondrial coupling and flux assay. By targeting these proteins and proteins upstream in the same pathway, we may be able to limit the development of HAND.

show abstract

Section: Methodsmentioning

confidence: 99%

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Not all studies, though, have uniformly detected such changes, and to some extent attribute a possible preservation of mitochondrial functional indices to compensatory responses [30]. …”

Section: Mitochondria and Agingmentioning

confidence: 99%

“…As a corollary to this, it has certainly been reported that compensatory mechanisms are initiated in the face of declining mitochondrial function and it must be considered how well these compensations mitigate the potential consequences of age-related changes in mitochondrial function and cell bioenergetics [30]. …”

Section: Mitochondria and Agingmentioning

confidence: 99%

Mitochondria, Cybrids, Aging, and Alzheimer's Disease

Swerdlow

Koppel

Weidling

et al. 2017

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

Mitochondrial and bioenergetic function change with advancing age and may drive aging phenotypes. Mitochondrial and bioenergetic changes are also documented in various age-related neurodegenerative diseases, including Alzheimer’s disease (AD). In some instances AD mitochondrial and bioenergetic changes are reminiscent of those observed with advancing age, but are greater in magnitude. Mitochondrial and bioenergetic dysfunction could, therefore, link neurodegeneration to brain aging. Interestingly, mitochondrial defects in AD patients are not brain-limited, and mitochondrial function can be linked to classic AD histologic changes including amyloid precursor protein processing to beta amyloid. Also, transferring mitochondria from AD subjects to cell lines depleted of endogenous mitochondrial DNA (mtDNA) creates cytoplasmic hybrid (cybrid) cell lines that recapitulate specific biochemical, molecular, and histologic AD features. Such findings have led to the formulation of a “mitochondrial cascade hypothesis” that places mitochondrial dysfunction at the apex of the AD pathology pyramid. Data pertinent to this premise are reviewed.

show abstract

“…A few studies have been reported where mitochondrial proteins have been examined in normal brain tissue [9, 10]. Existing studies of skeletal muscle senescence suggest that mitochondrial enzymes are largely increased in abundance, though how this information fits with decreased complex I activity in ageing mitochondria has not yet been determined [11].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration

Pollard

Shephard

Freed

et al. 2016

Aging

View full text Add to dashboard Cite

Carbonic anhydrase inhibitors are used to treat glaucoma and cancers. Carbonic anhydrases perform a crucial role in the conversion of carbon dioxide and water into bicarbonate and protons. However, there is little information about carbonic anhydrase isoforms during the process of ageing. Mitochondrial dysfunction is implicit in ageing brain and muscle. We have interrogated isolated mitochondrial fractions from young adult and middle aged mouse brain and skeletal muscle. We find an increase of tissue specific carbonic anhydrases in mitochondria from middle-aged brain and skeletal muscle. Mitochondrial carbonic anhydrase II was measured in the Purkinje cell degeneration (pcd5J) mouse model. In pcd5J we find mitochondrial carbonic anhydrase II is also elevated in brain from young adults undergoing a process of neurodegeneration. We show C.elegans exposed to carbonic anhydrase II have a dose related shorter lifespan suggesting that high CAII levels are in themselves life limiting. We show for the first time that the mitochondrial content of brain and skeletal tissue are exposed to significantly higher levels of active carbonic anhydrases as early as in middle-age. Carbonic anhydrases associated with mitochondria could be targeted to specifically modulate age related impairments and disease.

show abstract

Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism

Cited by 43 publications

References 60 publications

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution

Mitochondria, Cybrids, Aging, and Alzheimer's Disease

Mitochondrial proteomic profiling reveals increased carbonic anhydrase II in aging and neurodegeneration

Contact Info

Product

Resources

About