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Review
. 2022 Aug 16;23(16):9212.
doi: 10.3390/ijms23169212.

The Role of Bioenergetics in Neurodegeneration

Taylor A Strope  1   2 , Cole J Birky  1 , Heather M Wilkins  1   2   3
Affiliations
Review

The Role of Bioenergetics in Neurodegeneration

Taylor A Strope et al. Int J Mol Sci. .

Abstract

Bioenergetic and mitochondrial dysfunction are common hallmarks of neurodegenerative diseases. Decades of research describe how genetic and environmental factors initiate changes in mitochondria and bioenergetics across Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Mitochondria control many cellular processes, including proteostasis, inflammation, and cell survival/death. These cellular processes and pathologies are common across neurodegenerative diseases. Evidence suggests that mitochondria and bioenergetic disruption may drive pathological changes, placing mitochondria as an upstream causative factor in neurodegenerative disease onset and progression. Here, we discuss evidence of mitochondrial and bioenergetic dysfunction in neurodegenerative diseases and address how mitochondria can drive common pathological features of these diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; bioenergetics; mitochondria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mitochondrial-Cascade Hypothesis of AD. Inherited mtDNA determines baseline function for individuals. During aging, mitochondrial function declines and somatic mutations accumulate. If baseline function is low, mitochondrial dysfunction occurs earlier than if baseline function is high. Eventually, a functional threshold is reached where mitochondrial dysfunction leads to a cascade of loss of proteostasis (Aβ plaques, tau tangles), inflammation, and neuronal loss/degeneration.
Figure 2
Figure 2
Cytoplasmic Hybrids (Cybrids). Patient-derived platelets with mitochondria are fused with cells that lack mtDNA (ρ0 cells) using PEG (polyethylene glycol). The ρ0 cells are auxotrophic for pyruvate and uridine. After fusing platelets with ρ0 cells, pyruvate and uridine are withdrawn to select for cells that received mitochondria.
Figure 3
Figure 3
Mitochondrial Dysfunction in PD. Inherited mutations in genes encoding proteins for PINK1, Parkin, and α-synuclein affect mitochondrial function through the inhibition (red blunt arrow) of CI and/or mitophagy inhibition. Environmental factors, such as MPTP and pesticide rotenone, inhibit CI (orange blunt arrow). mtDNA (either inherited or somatic mutations) inhibit complex I (red blunt arroa). All factors lead to increased ROS, mitochondrial calcium, and the activation of the mitochondrial permeability transition pore (mPTP) with decreased bioenergetics and mitophagy.
Figure 4
Figure 4
Mitochondrial dysfunction in ALS. Inherited mutations in genes encoding proteins for TDP43 and SOD1 affect mitochondrial function through inhibition of bioenergetics and mitochondrial transport. Mutations in FUS inhibit ATP synthase or complex V (CV) and C9orf72 peptides interact with mitochondrial ribosomes and affect the expression of mtDNA encoded proteins (red blunt arrows). Environmental factors and head injuries affect overall mitochondrial function (orange blunt arrow). Furthermore, mtDNA (either inherited or somatic mutations) inhibits complex I (red blunt arrow). All these factors lead to increased ROS, mitochondrial calcium, and activation of the mitochondrial permeability transition pore (mPTP) with decreased bioenergetics.
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