Mitochondria, Cybrids, Aging, and Alzheimer's Disease

Abstract

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.

An Integrative Overview of Non-Amyloid and Non-Tau Pathologies in Alzheimer’s Disease

“…Mitochondrial dysfunction is seen in a number of neurodegenerative conditions including AD, Leber’s hereditary optic neuropathy(LHON), Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) [78], Mitochondria may account for observed relationships between advancing age and an age-related increase in the incidence of various neurodegenerative diseases, as mitochondrial function declines with advancing age [79], In various tissues, including the nervous system, somatic mutations accumulate within mitochondrial DNA (mtDNA), which may contribute to or compound age-related changes in mitochondrial function [80,81], Some have proposed declines in mitochondrial function that exceed a threshold can contribute to the onset or progression of neurodegenerative diseases [82,83], According to one scheme, an individual’s genetic inheritance helps to define a baseline level of mitochondrial function, and the rate at which that individual’s mitochondria decline over decades further determines how rapidly the individual approaches a functional threshold that allows for the manifestation of an age related disease such as AD [84]. …”

Clinical effects of chemical exposures on mitochondrial function

“…The contribution of mitochondrial dysfunction has been reported in major environment-related multifactorial diseases, such as respiratory disease (Bialas et al, 2016), viral infections (Wnek et al, 2016), neurological disorders (Giannoccaro et al, 2017, Swerdlow et al, 2017), cardiovascular diseases (Sabbah, 2016), and cancer (Srinivasan et al, 2017). Although harmful exposure to environmental pollutants is ubiquitous among all populations, disease manifestation occurs in only a subset of the population.…”

Mitochondrial tRNA methylation in Alzheimer’s disease and progressive supranuclear palsy

“…Though the genetic etiology of neurodegeneration is highly heterogeneous, there is an extensive literature implicating mitochondrial dysfunction as a common and early factor in the pathophysiology of a number of neurodegenerative diseases (1). Much of the mitochondrial genetic-centric studies of neurodegenerative diseases and related comorbidities have focused primarily on mitochondrial DNA (mtDNA) mutations, changes to mtDNA copy number and/or release of cell-free mtDNA (2); however, the significance of mitochondrial transcriptome epigenetics and altered mitochondrial RNA (mt-RNA) processing has not been explored.…”