Amyloid protein aggregates: new clients for mitochondrial energy production in the brain?

Abstract

Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitochondria support transcriptional regulation and proteostatic signaling mechanisms through crosstalk between the mitochondria itself, the nucleus, and the cytoplasm. Mitochondrial dysfunction leads to impaired proteostasis, and both are key pathological features of age-related neurological disorders. For example, Alzheimer's and Parkinson's diseases feature mitochondrial-targeted protein aggregates and impaired mitochondrial function, although the mechanistic causes are poorly understood. Vascular abnormalities and hypometabolism in such neurological diseases are reported several years before key clinical disease symptoms even become apparent. Recent investigations suggest that processing of such aggregates within mitochondria can offer protective functions, specifically by restoring energy (ATP) in starving cells. We hypothesize that the accumulation of protein aggregates in mitochondria can not only disrupt its functions, but also render a protective role to fulfill energy demands in hypometabolic conditions. Growing evidence favors mitochondrial defense to toxic amyloid aggregates/oligomers as a protective response. In this viewpoint article, we will present several publications (in addition to our own) that serve to connect the possible role of protein aggregates in mitochondrial energy production for degenerative conditions.

Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer’s Disease

“…CI-51kD, CIII-s2 and ATPase-d are components of the ETC complexes I, III, and V, respectively ( Figure 2 and Figure 3 ). The Kyoto Encyclopedia of Genes and Genomes (KEGG) database ( , accessed on 10 April 2021) reveals the involvement of these proteins in AD pathways, as also supported by the extensive literature on energy metabolism impairment and mitochondrial dysfunction in AD [ 42 , 43 , 44 ].…”

Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer’s Disease: A Critical Review of New and Old Little Regarded Findings

“…Growing evidence suggests that the accumulation of APP and Aβ in synaptic mitochondria from post-mortem AD brains, as well as cellular and transgenic mouse models [146][147][148], due to interactions with proteins essential for proper organelle function [79,83,[149][150][151], causes both structural and functional mitochondrial damage, triggers synaptic lesions, interrupting synaptic transmission [152,153], and ultimately prevents neurons from functioning normally [154] (Figure 2). This means that the approach to curb the accumulation of Aβ in the mitochondria may have great pharmaceutical potential.…”

Mitochondria-Microbiota Interaction in Neurodegeneration

“…The same is true for the amyloids typically implicated in Alzheimer’s and Parkinson’s ( Moir et al, 2018 ; Barbut et al, 2019 ). Healthy mitochondria degrade damaged or misfolded proteins, including amyloids like alpha-synuclein and beta-amyloid, but they become overwhelmed when amyloid concentrations become too high ( Lautenschäger and Schierle, 2019 ; Lautenschäger et al, 2020 ; Sivanesan et al, 2020 ). Moreover, mitochondria release free radicals – chemicals that are corrosive to their host but also to their own mitochondrial DNA.…”

“…Moreover, mitochondria release free radicals – chemicals that are corrosive to their host but also to their own mitochondrial DNA. As a result, over time, more and more of these mitochondria become dysfunctional ( Lane, 2015 ; Kramer and Bressan, 2019 ) and eventually unable to detoxify the amyloids ( Sivanesan et al, 2020 ).…”