Table 1 Mitochondrial deficiencies associated with brain degenerative disorders

Alzheimer's disease (AD)

n.d

Metabolic enzyme dysregulation, favoring the accumulation of tau tangles and Aβ plaques

Non-neural cell types obtained from AD patients

[35,36,37]

Increased expression of apoptotic markers

Reduced mitochondrial membrane potential, decreased ATP levels and oxygen consumption

Human neuroblastom a SH-SY5Y non-nucleated cells transplanted with platelet- derived cytoplasm from AD patients

[45]

Rotenone- induced complex I inhibition

Loss of neurons in the substantia nigra and the striatum, cytoplasmic accumulations of phosphorylated tau. Decrease in ATP levels

Rat

[46, 47]

Accumulating mitochondrial DNA polymerase mutation

Severe mitochondrial bioenergetic defects

Transgenic mice expressing human AßPP

[48]

Reduced expression of AßPP and COX1

Forebrain and hippocampal region atrophy. Reduced Aß plaque frequency and reduction of 8OHG⁺ nuclei

COX deficient mice

[49]

Parkinson's disease (PD)

Complex 1 inhibition

Nigral neuron degeneration

SH-SY5Y cells Rats treated with rotenone

[62, 63]

Nrf2/Keap1 signaling

Abnormal thermal profile, increased

Mice, rats, and C. elegans

[65, 66]

Pathway

Oxidative stress, and abnormal dopamine dependent behavior. Mitochondrial related neuronal apoptosis and motor defects

Treated with 6- OHDA

Severe mt-DNA damage

Elevated levels of co-enzyme Q-10 and 8-OHdG on nigral neurons

Post-mortem samples from PD patients

[71, 72]

MEF2D binding to mt-DNA sections encoding complex I subunit NADH dehydrogenase

Increased hydrogen peroxide levels, low ATP production and stress-induced cell death

Mice and post mortem PD brains

[75, 76]

Expression levels of mitochondrial complexes III subunit UQCR2, IV and V subunit ATP5A

Reduced intracellular ATP content

LrrkG2019S knock-in mice and patient- derived fibroblasts

[77]

Parkin mutation

Reduced mitochondrial complex I activity and intracellular ATP content

Human fibroblasts, drosophila and zebrafish

[79,80,81]

Premature stop mutation (Y431*)

Dysfunction of mitochondrial complexes I and III, and loss of dopaminergic neurons

PINK1 mutant zebrafish

[81]

Down-regulation of various electron carrier proteins

Low complex I- mediated respiration

PINK1 KO rats

[83]

Huntington's disease (HD)

Decrease in CAG repeats

Decrease in ATP content, and respiratory and glycolytic capacities

iPSC-derived from patient fibroblasts

[92]

Dysregulation of mitochondrial encoded genes associated with electron transport chain subunits

Mitochondrial swallow, loss of cristae organization, suppression of complex III activity and ATP production

Wistar rats exposed to mitochondrial toxins

[93,94,95]

Approximately 145 CAG repeats, downregulation of mitochondrial membrane related proteins

Mitochondrial membrane potential and calcium influx are diminished

R6/1 primary striatal neuron

[96]

Down-regulation of the expression of fusion markers and mitochondrial biogenesis regulators Upregulation of fission markers

Decrease in mitochondrial fragments and ATP generation. Increase in GRPase-DRP1 activity and hydrogen peroxide levels

HdhQ111/Q11 1 neurons

[94, 95]

Increased oxidative stress markers and reduced expression of mitochondrial biogenesis mediators

Increase in autophagy and ubiquitination of mitochondrial constituents

R6/2 HD mice

[97]

Mutant Htt interacting with VCP

Mitochondrial fragmentation and increase in mitophagy

Flag-mtVCP- expressing striatal and spiny neurons from R6/2 and YAC128 mice

[98]

Transgenic expression of human full length Htt (Q⁹⁷). Htt binding with Drp1

Increase in nitric oxide and S- nitrosylation. Promotion of mitochondrial fragmentation and dendritic spine density

BACHD transgenic rats and postmortem brain samples from HD patients

[89]

Multiple

Disturbed

Calcium

Brain tissue

[122]

Sclerosis (MS)

Oxidative phosphorylation, activation of calcium- dependent proteases

Accumulation, cytoskeletal modifications, and impaired axonal integrity

From patients autopsy

Dysregulation of the expression of H3K3me3

Change in chromatin dynamics and thus poor transcription of mitochondrial genes

Human SH- SY-5Y neuroblastom a cells

[127]

Sirtuin deregulation and Rab32- mediated ER stress

Mitochondrial dysfunction and thus progressive neuronal death and MS severity

Primary human fetal neurons

[116]

n.d

Low respiratory capacity, poor mitochondrial mass and reduced proliferative potential

Peripheral blood cells of MS patients

[114]

Down-regulation of mitochondrial biomass markers

Ultrastructural mitochondrial abnormalities

Naïve and effector memory CD4⁺ T cells from MS patients

[114]

Friedreich's ataxia (FA)

Frataxin knock- down, up- regulation of SOD1/2 enzymes

Disturbances in mitochondrial membrane potential and dynamics, elevated protein carbonylation and poor reductive capacity, increased lipid droplet formation

Non-neural cells

[138, 139]

n.d

Glutathione- dependent mitochondrial oxidative stress and thiol modifications in respiratory chain

Frataxin deficient lymphoblasts

[140, 141]

complexes III and IV

Depletion of frataxin expression

Poor neuronal cell area in the dorsal root ganglia

Frataxin- deficient knockin- knockout (Cg- Fxntm1MknFx ntm1Pand/J; KIKO) mice

[144]

Single GAA repeat sequence in the frataxin gene

Reduced mitochondrial membrane potential, exacerbated ROS generation, defects in the activity of mitochondrial complexes I, II, III and IV, and increased lipid peroxidation and neuronal death

YG8R mice

[146]