Mitochondrial dysfunction associated with NI&NDDs is also facilitated by pathological accumulation of specific aberrant proteins as a result of nuclear gene mutations or abnormal protein processing leading to oligomeric and fibrillary aggregates. The anomalous accumulation of protein aggregates impacts mitochondrial structure and function either due to altered interaction with other subcellular organelles or dysregulation of processes involved in mitochondrial dynamics. The main protein aggregates related to proteinopathies are: amyloid β (Aβ) peptide and Tau protein in AD
[68,69,70,71][68][69][70][71]; α-synuclein (α-syn) in PD
[72[72][73][74],
73,74], transactive response DNA-binding protein of 43 kDa (TDP-43) in AD and ALS
[61,75,76][61][75][76]; Cu, Zn-superoxide dismutase (SOD1) in ALS
[77,78][77][78]; and Huntingtin protein (Htt) in HD
[50,79,80][50][79][80].
Table 1 summarizes the evidence relating these protein aggregates with mitochondrial dysfunction in ND diseases. α-Syn is a neuronal protein associated with the release of neurotransmitters and synaptic vesicles
[81], and its misfolding and aggregation in structures referred to as Lewy bodies, particularly in dopaminergic neurons, is a hallmark of PD
[81,82][81][82]. α-syn interaction with the mitochondrial structure is associated with an impairment of ETC activity, decreased MMP, mPTP opening and mitochondrial swelling as well as increased levels of mitochondrial ROS and neuron cell death
[73,74][73][74]. In addition, α-syn interferes with the mitochondrial contacts with ER, leading to the disruption of Ca
+2 flux and a reduction of ATP production
[83]. Additionally, α-syn association with mitochondria results in downregulation of the predominant SIRT in the mitochondria (SIRT3)
[72], which is a molecule that protects mitochondrial integrity and energetic function
[84]. SIRT3 reduction is also accompanied by an increased expression of the fission protein DRP1 in neural cells and brain tissue of mice expressing α-syn
[73]. α-Syn is also upregulated in the neurons and glia of demyelinating lesions in the spinal cord of mice developing EAE
[85,86][85][86]. Moreover, the levels of α-syn in the cerebrospinal fluid of MS patients correlates with disease disability, suggesting a participation of α-syn in demyelinating and NI pathologies
[87]. The intracellular accumulation of aggregates of Aβ peptide and hyperphosphorylated protein Tau are biochemical characteristics of AD
[71,88,89][71][88][89]. The Aβ peptide derives from amyloid precursor protein (APP) in the mitochondria–ER contacts through sequential processing by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase
[90]. Aβ interacts with mitochondrial molecules and structures, which results in ROS production, mitochondrial dysfunction, and subsequent cell damage
[91,92,93,94][91][92][93][94]. In addition, Aβ alters mitochondrial morphology and fragmentation by increasing DRP1 and reducing Mfn1 levels in cellular models
[68,94][68][94]. Moreover, the mitochondrial fission promoted by Aβ occurs through
O-GlcNAcylation of DRP1 in both neuronal cell lines and primary cultured neurons
[69]. Interestingly, the activated form of DRP1 by
O-GlcNAcylation is also found in the brains of mice in an AD mouse model
[69]. Tau is a microtubule-binding protein in neurons, and its abnormal processing and aggregation by hyperphosphorylation promotes dissociation of preformed microtubules, interaction with mitochondrial ETC complexes, reduction of ATP production, and neuronal death
[71,93][71][93]. In addition, hyperphosphorylated Tau interacts with VDAC1 mitochondrial protein promoting the alteration of energetic functions, Ca
+2 homeostasis, and oxidative balance
[71,91][71][91]. In addition, Tau alters mitochondrial fission and mitophagy by interacting with DRP1 and PARKIN proteins, respectively, in both patients and transgenic mouse models of AD
[70,93][70][93]. TDP-43 is an essential ribonucleoprotein that can also form toxic cytosolic aggregates in AD. Diverse mutated forms of TPD-43 have been localized as aggregates in the mitochondria of mouse models and patients with familial ALS and are associated with structural and functional alterations in mitochondria
[61,95,96][61][95][96]. Consistently, the inhibition of mitochondrial localization of TDP-43 restored mitochondrial function and ameliorated motor and cognitive deficits in ALS and AD models
[75,76,97][75][76][97]. In HD, the generation of a mutated huntingtin protein (mHTT) by abnormal expansion of a CAG polyglutamine trinucleotide
[98] impacted mitochondrial function and subsequent ND processes
[50,79,80][50][79][80]. The enzyme SOD1 is mainly a cytosolic molecule, but mutated forms of SOD1 have been localized in aggregates associated with mitochondria in transgenic mouse models and patients with familial ALS
[77,78][77][78]. Interestingly, the pharmacological reduction of misfolded SOD1 restored the structural integrity of mitochondria, reduced degeneration of motor neurons, and attenuated motor deficits in a transgenic ALS mouse model
[99].
Table 1. Protein aggregates related to mitochondrial dysfunction in models of neurodegenerative diseases.
Protein Aggregates |
Disease Model |
Effect on Mitochondria |
Refs |
α-synuclein |
PD |
↑mitochondrial ROS levels, ↓ ETC activity, ↓stability of mitochondrial membranes, ↑mPTP opening, ↓mitochondria-ER contacts, ↑DRP1 and ↓mitochondrial SIRT3 levels (a protective molecule of mitochondrial integrity and energetic function [84]) |
[72,,100] | [72 | 73, | ][73 | 74, | ][74] | 83 | [83][100] |
Amyloid b |
AD |
↑mitochondrial ROS levels, ↑mitochondrial fission (↓Mfn1, ↑DRP1 levels and ↑O-GlcNAcylation of DRP1) |
[68,69, | 68][ | 91,
| 69] | 92, | [91] | 94] | [ [92][94] |
Tau |
AD |
↑microtubule dissociation, ↑mitochondrial ROS levels, ↓ATP production, ↑mitochondrial fission and ↓mitophagy (interaction with DRP1 and PARKIN proteins) |
[70,71,93] | [70][71][93] |
Transactive response DNA-binding protein of 43 kDa (TDP-43) |
AD, ALS |
↑mitochondrial ROS levels, ↓stability of mitochondrial structure, ↑mPTP opening |
[61,75,95,96,97] | [61][75][95][96][97] |
Huntingtin |
HD |
↑mitochondrial ROS levels, ↓stability of mitochondrial structure, ↑mPTP opening, ↑mitochondrial fission by activation of DRP1, ↓mitophagy, ↑disruption Ca | +2 | flux between ER and mitochondria |
[49,101] | [49] | 79, 80, | [79] [80][101] |
Superoxide dismutase |
ALS |
↓mitophagy (by arresting optineurin protein), ↓stability of mitochondria structure, ↓flux of protein from and to the mitochondria |
[102,103,104,105] | [102][103][104][105] |