Table 2.

Summary of import defects associated with neurodegenerative diseases and their consequences on respiratory complexes.

Pathology	Import Defect(s)	Known Consequence(s)	Model Organism/System	Reference
Alzheimer’s Disease	APP accumulation in Tom40 and Tim23 channels, with higher levels in AD susceptible brain regions.	Inhibition of import of CIV 4 and 5b, and subsequent reduction in CIV activity, leading to increased ROS.	Human AD brains.	[260]
	Chronic, sub-lethal Aβ exposure induces a significant reduction in mitochondrial protein import.	Reduction in Δψ, altered mitochondrial morphology, and increased ROS production.	PC12 cells.	[261]
	Tau accumulation in OMM and IMS, and interactions between N-terminal Tau fragment with OPA1 and Mfn1.	N/A	HEK293T cells, HeLa cells.	[262,263]
Parkinson’s Disease	α-syn localises to and accumulates within mitochondria, mediated by a cryptic non-canonical MTS, in an ATP and Δψ dependent manner	N/A	Human dopaminergic neuronal cultures, PD brains.	[264]
	A53T version of α-syn is imported more efficiently than wildtype variant.	May account for faster development of cellular abnormalities seen in cells expressing the A53T version of α-syn compared to the wildtype.	Human dopaminergic neuronal cultures, PD brains, A53T mutant alpha-synuclein-inducible PC12 cell lines.	[265,266]
	Mitochondrial α-syn accumulates at IMM and interacts with CI.	Reduction in CI activity, increase in ROS production, inducing oxidative stress.	Human dopaminergic neuronal cultures, PD brains, rat SN neurons, human neuroblastoma cell line (SK-N-MC cells).	[266]
	S129 phosphorylated α-syn binds tightly to Tom20, inducing loss in Tom20-Tom22 interaction.	Impaired protein import, loss of Δψ, reduced respiratory capacity, and increased oxidative stress. Rescued by in vivo knockdown of endogenous α-syn, and by in vitro Tom20 overexpression.	SH-SY5Y cells and dopaminergic neurons from SN of post-mortem PD patient brains.	[267]
	Tom40 downregulation, corresponding with α-syn accumulation in PD brains.	N/A	Midbrain of PD patients and α-syn transgenic mice.	[268]
	Excessively low levels of mitochondrial import in cells from PINK1- and PARK2-linked PD patients.	N/A Import defects reversed by phosphomimetic ubiquitin in cells with residual Parkin activity.	Cells from PINK1- and PARK2-linked PD patients.	[27]
Huntington’s Disease	Disease variant Htt localises to mitochondria and directly interacts with the TIM23 complex.	Inhibited import and subsequent respiratory dysfunction, triggering cell death, rescued by TIM23 overexpression.	Isolated mitochondria from human HD brains, primary neurons expressing Htt variant, forebrain synaptosomal mitochondria in HD mice at early stages of HD.	[269]
	Dysfunctions in MIA pathway associated with mutant Htt: reduced levels and ratio of Erv1 and Mia40.	Reduced import of MIA pathway precursors, CIV assembly defects, deficient respiration, alterations in mtDNA, altered mitochondrial morphology.	Neuronal cell lines.	[270]
Amyotrophic Lateral Sclerosis	Variants of SOD1 accumulate in IMS, matrix, and OMM, and interact with OMM proteins.	Excessive ROS production, mitochondrial dysfunction, and toxic effects on the cells rescued by selective IMS targeting of wildtype SOD1.	Transgenic mouse models, spinal cord mitochondria.	[271,272,273]
	Increased levels of TOM subunits Tom20, Tom22, and Tom40. Overall reduction in import efficiency by 30%.	Changes in CI related protein expression levels.	Rat spinal cord of ALS-linked variant SOD1G93A.	[274]
	Novel CHCHD10 mutant, Q108P, discovered in a patient with rapidly progressing ALS, almost completely abolishes its import.	Reduced mitochondrial respiratory capacity, an effect that is rescued by Mia40 overexpression.	HeLa cells and primary rat embryonic neurons transduced with genomic DNA from a young ALS patient.	[275]