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Review
. 2020 May 29;15(1):30.
doi: 10.1186/s13024-020-00376-6.

Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances

Wenzhang Wang  1 , Fanpeng Zhao  2 , Xiaopin Ma  2 , George Perry  3 , Xiongwei Zhu  4
Affiliations
Review

Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances

Wenzhang Wang et al. Mol Neurodegener. .

Abstract

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

Keywords: Alzheimer’s disease; Axonal transport; Bioenergetics; ER-mitochondria association; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial proteostasis; Mitochondrial quality control; mtDNA.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Critical role of mitochondrial dysfunction in AD. Mitochondrial dysfunction plays a critical role in AD either as a primary or secondary event. In either case, impaired mitochondrial bioenergetics, increased oxidative stress and disturbed mitochondrial genome are consistent features of mitochondrial abnormalities in AD, all which interact with each other to form a deleterious downward spiral. While the relative importance of these abnormalities in triggering mitochondrial dysfunction may vary among patients with AD depending on the unique biological, environmental and genetic factors of each individual, any of these abnormalities could induce the other two to complete the downward spiral to mediate and amplify neuronal dysfunction and neurodegeneration. Recent studies revealed mechanisms underlying the loss of integrity of mitochondria, which provides mechanistic link among these abnormalities and offers multiple novel intervention sites to improve mitochondrial function in AD
Fig. 2
Fig. 2
Abnormal mitochondrial fusion and fission in AD. (Top) A family of large GTPases regulate balanced mitochondrial fusion (e.g. Mfn1/2, OPA1) and fission (DLP1). For mitochondrial fission, mitochondrial outer membrane proteins (e.g. Fis1, Mff and others) recruit cytosolic DLP1 protein to mitochondria that oligomerize and form a ring structure around fission site. (Bottom) Amyloid-β and other AD related insults cause neuronal calcium influx and increased ROS production that activate downstream proteases (calpain) and protein kinase that act on mitochondrial fission/fusion GTPases and disturb mitochondrial fusion and fission in AD
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