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 dysfunctions Evidence References Bioenergetic failure TCA cycle impairment Pyruvate dehydrogenase complex ↓ [54, 55, 58] Transketolase ↓ [55] Alpha-ketoglutarate dehydrogenase complex ↓ [55-58] Isocitrate dehydrogenase ↓, Succinate dehydrogenase ↑, and Malate dehydrogenase ↑ [58] ETC impairment Complex 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 stress Complex 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 damage mtDNA mutations at T477C, T146C & T195C [107] Non-specific damage mtDNA mutations stay at heteroplasmic state and accumulates until energy production impairs [111, 112] Ca2+ dysregulation Ca2+ influx ↑ from extracellular & endoplasmic reticulum to cytosol upon excitotoxicity [92, 113-115] Ca2+ influx ↑ into mitochondria via mPTP [116] Defective morphology and dynamics Fission ↑ 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 mitophagy PINK1 ↓ and parkin ↓, leading to autophagosomes ↓ and dysfunctional lysosomes ↑ [130]; Reviewed in [22, 23] Membrane permeabilisation mPTP 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]