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] |