A mitochondrial bioenergetic etiology of disease

Wallace, Douglas C.

doi:10.1172/jci61398

Cited by 270 publications

(273 citation statements)

References 96 publications

(103 reference statements)

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“…Systemic defects in mitochondrial bioenergetics occur in primary mitochondrial disorders, as well as in various age-related human disorders, including diabetes mellitus, cardiovascular disease, Alzheimer's and Parkinson's diseases, and cancer (1). To investigate the role of mitochondrial function in these diseases, it is essential to measure mitochondrial energy production in vivo, ideally with noninvasive tools.…”

Section: Introductionmentioning

confidence: 99%

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

DeBrosse¹,

Nanga²,

Wilson³

et al. 2016

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

DeBrosse¹,

Nanga²,

Wilson³

et al. 2016

JCI Insight

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“…We found a strong mitigating effect of haplogroups K and T on the effect of aging on TBI outcome. The observed effect of haplogroup K is compatible with its reduced ROS output compared to other haplogroups 20. The effect of haplogroup T is less clear, but it is of note that, similarly to haplogroup K, haplogroup T has been found to be under‐represented in neurodegenerative conditions 4.…”

Section: Discussionmentioning

confidence: 70%

“…Our results point to a protective effect of haplogroup K. The enzymatic components of the mitochondrial electron transport chain (ETC) encoded by haplogroup K are reported to be less tightly coupled than corresponding variants in other haplogroups, which reduces ROS production as a byproduct of adenosine triphosphate (ATP) synthesis 20. ROS are key mediators of secondary cell damage after a neurological insult, including TBI 29,30 ; it is therefore unsurprising that a less tightly coupled ETC may confer a cell survival advantage after injury.…”

Section: Discussionmentioning

confidence: 72%

Mitochondrial DNA and traumatic brain injury

Bulstrode

Nicoll

Hudson

et al. 2014

Annals of Neurology

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ObjectiveTraumatic brain injury (TBI) is a multifactorial pathology with great interindividual variability in response to injury and outcome. Mitochondria contain their own DNA (mtDNA) with genomic variants that have different physiological and pathological characteristics, including susceptibility to neurodegeneration. Given the central role of mitochondria in the pathophysiology of neurological injury, we hypothesized that its genomic variants may account for the variability in outcome following TBI.MethodsWe undertook an analysis of mitochondrial haplogroups in a large, well‐characterized cohort of 1,094 TBI patients. A proportional odds model including age, brain computed tomography characteristics, injury severity, pupillary reactivity, mitochondrial haplogroups, and APOE was applied to Glasgow Outcome Score (GOS) data.ResultsmtDNA had a significant association with 6‐month GOS (p = 0.008). Haplogroup K was significantly associated with favorable outcome (odds ratio = 1.64, 95% confidence interval = 1.08–2.51, p = 0.02). There was also a significant interaction between mitochondrial genome and age (p = 0.002), with a strong protective effect of both haplogroups T (p = 0.015) and K (p = 0.017) with advancing age. We also found a strong interaction between APOE and mitochondrial haplogroups (p = 0.001), indicating a protective effect of haplogroup K in carriers of the APOE ε4 allele.InterpretationThese findings reveal an interplay between mitochondrial DNA, pathophysiology of TBI, and aging. Haplogroups K and T, which share a common maternal ancestor, are shown as protective in TBI. The data also suggest that the APOE pathways interact with genetically regulated mitochondrial functions in the response to acute injury, as previously reported in Alzheimer disease. Ann Neurol 2014;75:186–195

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“…However, a large body of work has established additional and synergistic roles of the mitochondria in the regulation of cellular homeostasis. (142) Mitochondrial dysfunction is considered a hallmark of aging (143), and is implicated in apoptosis, senescence, genome instability, inflammation, and metabolic disorders (142,144). The term "mitophagy" was first coined by Dr. Lemasters (149), as well as normal physiological aging (150).…”

Section: Mitochondrial -Lysosomal Dysfunction In Nddmentioning

confidence: 99%

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

2018

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B ACKGROUND:Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme-Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases (NDDs). CONTENT:The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of NDDs. In Alzheimer's disease, the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism, corruptive protein templating. The accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. Autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival.SUMMARY: Senescent cells and their senescenceassociated secretory phenotypes (SASPs) may constitute a novel, understudied, and potentially important contributor to neuro-inflammation and subsequent neurodegeneration. Characterization of cellular senescence in the brain could uncover novel therapeutic targets for the prevention and treatment of chronic age-related NDDs. KEYwORDS

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A mitochondrial bioenergetic etiology of disease

Cited by 270 publications

References 96 publications

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

Mitochondrial DNA and traumatic brain injury

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

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