The role of mitochondrial dysfunction in age-related diseases

Lane, Rebecca; Hilsabeck, Tyler A.; Rea, Shane L.

doi:10.1016/j.bbabio.2015.05.021

Cited by 179 publications

(150 citation statements)

References 196 publications

(52 reference statements)

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“…Mitochondrial dysfunction directly causes multiple inherited diseases (1) and is implicated in common diseases, including neurological developmental disorders (2,3), neurodegenerative and cardiovascular diseases (4)(5)(6), diabetes (7), asthma (8), cancer (9), and age-related disease (10). In mammals, these organelles have evolved to retain more than 1,000 proteins that interact within a complex, i.e., dual membrane architecture (11,12).…”

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confidence: 99%

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Schweppe

Chavez

Lee

et al. 2017

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

174

206

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Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly. mitochondria | mass spectrometry | interactome | cross-linking | protein interaction reporter M itochondrial proteins play a diverse role in cellular biology and disease. Mitochondrial dysfunction directly causes multiple inherited diseases (1) and is implicated in common diseases, including neurological developmental disorders (2, 3), neurodegenerative and cardiovascular diseases (4-6), diabetes (7), asthma (8), cancer (9), and age-related disease (10). In mammals, these organelles have evolved to retain more than 1,000 proteins that interact within a complex, i.e., dual membrane architecture (11,12). Within the mitochondrial proteome, the "powerhouse" functions are carried out by the core constituents of the oxidative phosphorylation (OXPHOS) system [complexes I-IV of the electron transport chain (ETC) and ATP synthase (complex V)]. These proteins are necessary for creation of the mitochondrial electrochemical gradient that powers synthesis of ATP. This system includes critical protein-protein interactions within individual OXPHOS complexes as well as "supercomplex" interactions between ETC complexes I, III, and IV in the respirasome (13). Deficient supercomplex formation has been proposed as a critical mitochondrial defect in failing hearts (5,6,14,15), and dynamic rearrangement of supercomplexes has been implicated in noncanonical mitochondrial functions such as antibacterial innate immune responses (16). Assessing these interactions is further complicated by regulatory posttranslational modification and conformational changes of mitochondrial proteins (17)(18)(19)(20). Advances in this area have been impeded, in part, by the lack of large-scale detection of dynamic, sometimes transient, interactions between membrane proteins. Thus, large-scale determination of the protein interactome within mitochondria would provide a valuable tool to adv...

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mentioning

confidence: 99%

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Schweppe

Chavez

Lee

et al. 2017

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

174

206

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“…Depletion of stem cells in various tissues, mitochondrial dysfunction, and decline in immune system functions (immunosenescence) contribute to weakened allostatic potential. 28,145 Mitigating effects promoting ''successful aging'' include diet and psychosocial parameters, such as social networks and ''happiness. '' 111 These factors may also play a role in successful aging of apes, as ''happy'' orangutans seem to live longer.…”

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confidence: 99%

Comparative Pathology of Aging Great Apes

2015

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The great apes (chimpanzees, bonobos, gorillas, and orangutans) are our closest relatives. Despite the many similarities, there are significant differences in aging among apes, including the human ape. Common to all are dental attrition, periodontitis, tooth loss, osteopenia, and arthritis, although gout is uniquely human and spondyloarthropathy is more prevalent in apes than humans. Humans are more prone to frailty, sarcopenia, osteoporosis, longevity past reproductive senescence, loss of brain volume, and Alzheimer dementia. Cerebral vascular disease occurs in both humans and apes. Cardiovascular disease mortality increases in aging humans and apes, but coronary atherosclerosis is the most significant type in humans. In captive apes, idiopathic myocardial fibrosis and cardiomyopathy predominate, with arteriosclerosis of intramural coronary arteries. Similar cardiac lesions are occasionally seen in wild apes. Vascular changes in heart and kidneys and aortic dissections in gorillas and bonobos suggest that hypertension may be involved in pathogenesis. Chronic kidney disease is common in elderly humans and some aging apes and is linked with cardiovascular disease in orangutans. Neoplasms common to aging humans and apes include uterine leiomyomas in chimpanzees, but other tumors of elderly humans, such as breast, prostate, lung, and colorectal cancers, are uncommon in apes. Among the apes, chimpanzees have been best studied in laboratory settings, and more comparative research is needed into the pathology of geriatric zoo-housed and wild apes. Increasing longevity of humans and apes makes understanding aging processes and diseases imperative for optimizing quality of life in all the ape species.

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“…Alterations in mtDNA are well known to involve a wide variety of energy metabolism 18 and aging-associated diseases, 19 such as atherosclerosis, diabetes 20 and cancer. 21 Because mtDNA usually presents with heteroplasmy, a quantitative analysis to determine the proportion and types of mtDNA alterations is critical for diagnosing disease and for assessing how to treat it.…”

Section: Resultsmentioning

confidence: 99%

Handheld energy-efficient magneto-optical real-time quantitative PCR device for target DNA enrichment and quantification

Chang

et al. 2016

NPG Asia Mater

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A PCR provides not only valuable genetic information that enables precise differential disease diagnosis but also quantitative data to assess various clinical states. We report the successful integration of novel dual-mode magnetic Fe 3 O 4 nanoclusters that deliver photothermal conversion. The clusters can be excited with pulsed laser light for precision thermal cycle modulation to develop an ultrafast quantitative PCR system. Traditional PCR heats and cools the sample from outside the PCR tube; the heat needs to pass through the heat block, tube wall and transfer to the DNA through water molecules. In contrast, our system uses nanoparticles inside the liquid phase as numerous 'nanoheaters'; thus the thermal transfer between particles and adjacent water or DNA molecules becomes extremely efficient because of proximity at the molecular level. Moreover, the defective mitochondrial DNA from cybrid cell lines of a patient with chronic progressive external ophthalmoplegia syndrome, a mitochondrial disease, was efficaciously detected. The system has a simple design, is extremely energy efficient and is faster than traditional qPCR. Our finding provides new insight into rapid and accurate quantitative diagnostics for future point-of-care applications.

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The role of mitochondrial dysfunction in age-related diseases

Cited by 179 publications

References 196 publications

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Mitochondrial protein interactome elucidated by chemical cross-linking mass spectrometry

Comparative Pathology of Aging Great Apes

Handheld energy-efficient magneto-optical real-time quantitative PCR device for target DNA enrichment and quantification

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