Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease
Wong Kan Yin, Roy Jaydeep, Fung Man Lung, Heng Boon Chin, Zhang Chengfei, Lim Lee Wei
Table 1 Summary of specific types of mitochondrial dysfunctions in Alzheimer’s disease.
Mitochondrial dysfunctionsEvidenceReferences
Bioenergetic failure
TCA cycle impairmentPyruvate dehydrogenase complex ↓[54, 55, 58]
Transketolase ↓[55]
Alpha-ketoglutarate dehydrogenase complex ↓[55-58]
Isocitrate dehydrogenase ↓,
Succinate dehydrogenase ↑, and Malate dehydrogenase ↑
[58]
ETC impairmentComplex IV ↓[20, 59-61]
Haem-a (structural component of complex IV) ↓[62-64]
Transmembrane arrest of TOMM40 & TIM23 pores[65-67]
Complex I ↓ due to phosphorylated tau[20]
Complex V Dysregulation[68, 69]
Oxidative stressComplex IV ↓ with complex III remains intact or ↑[71]
Oxidative scavengers (SOD, GPx & GSH) ↓[72, 73]
Reactive oxygen species level ↑[71, 74-76]
↑Peroxidation of Aβ-bind alcohol dehydrogenase in H2O2[25, 77, 78]
Peroxidation by haem-Aβ complexes ↑[79, 80]
mtDNA damage
Specific damagemtDNA mutations at T477C, T146C & T195C[107]
Non-specific damagemtDNA mutations stay at heteroplasmic state and accumulates until energy production impairs[111, 112]
Ca2+ dysregulationCa2+ influx ↑ from extracellular & endoplasmic reticulum to cytosol upon excitotoxicity[92, 113-115]
Ca2+ influx ↑ into mitochondria via mPTP[116]
Defective morphology and dynamicsFission ↑ with fusion ↓, possibly related to corresponding genes[108, 119-121]
Size changes (smaller, spherical, swollen, and/or elongated)[118, 120, 121]
Mitochondrial transport to synaptic terminal ↓[125]
Cristae ↓ and paler matrix[120]; Reviewed in [118]
Mitophagy ↑ due to phosphorylated tau[22]
Defective mitophagyPINK1 ↓ and parkin ↓, leading to autophagosomes ↓
and dysfunctional lysosomes ↑
[130]; Reviewed in [22, 23]
Membrane permeabilisationmPTP opening ↑ with cyt c release[131, 132]
Aβ bind to VDAC ↑ leading to mPTP opening ↑[123]
TrkA receptor on cell membrane ↓
Extracellular proNGF ↑ Results: pro-apoptotic signalling ↑, and mPTP opening ↑
[135-137]