Table 1.

Pathological consequences of TOM import defects^a

Pathology	Import defect(s)	Known consequence(s)	Model organism/system
Alzheimer’s disease (AD)	APP accumulation in Tom40 and Tim23 channels, with higher levels in AD susceptible brain regions.	Inhibition of import of respiratory complex IV (CIV) 4 and 5b and subsequent reduction in CIV activity, leading to increased ROS.	Human AD brains.
	Chronic, sublethal Aβ exposure induces a significant reduction in mitochondrial protein import.	Reduction in Δψ, altered mitochondrial morphology, and increased ROS production.	PC12 cells.
	Tau accumulation in OMM and IMS and interactions between N-terminal Tau fragment with OPA1 and Mfn1.	N/A	HEK293T cells, HeLa cells.
Parkinson’s disease (PD)	α-Syn localizes to and accumulates within mitochondria, mediated by a cryptic noncanonical MTS, in an ATP- and Δψ-dependent manner	N/A	Human dopaminergic neuronal cultures, PD brains.
	A53T version of α-syn is imported more efficiently than WT variant.	May account for faster development of cellular abnormalities seen in cells expressing the A53T version of α-syn compared to the WT.	Human dopaminergic neuronal cultures, PD brains, A53T mutant α-syn–inducible PC12 cell lines.
	Mitochondrial α-syn accumulates at IMM and interacts with respiratory complex I (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).
	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 postmortem PD patient brains.
	Tom40 downregulation, corresponding with α-syn accumulation in PD brains.	N/A	Midbrain of PD patients and α-syn transgenic mice.
	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.
Huntington’s disease (HD)	Disease variant HTT localizes 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.
	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.

Abbreviations: α-syn, α-synuclein; APP, amyloid precursor protein; HTT, Huntingtin gene; Mfn1, mitofusin-1; mtDNA, mitochondrial DNA; MTS, mitochondrial targeting signal; OPA1, optic atrophy type 1; PARK2, parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN-induced putative kinase; ROS, reactive oxygen species.

^aContents obtained from and reproduced with permission from Needs et al. (2021) (187).