Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines

Abstract

Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD+/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1α, PGC1α, SIRT1, AMPK, p38 MAPK and mTOR. Several endpoints suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission-fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences.

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease

“…In AD, mitochondrial dysfunction precedes detectable amyloid pathology in humans[5–7] and animal models[8, 9]. The origin and underlying cause of mitochondrial dysfunction in AD has not been identified, but it has been linked to altered expression of bioenergetics genes[10, 11], exposure to environmental toxins[12–14], mutations in mitochondrial DNA[15, 16], oxidative damage[17], and accumulation of ApoE ε4 fragments[18–20] and/or beta-amyloid peptides in the mitochondrial matrix[21–26]. Mitochondria possess approximately 1500 proteins, and nuclear genes encode greater than 95% of these, which are synthesized on cytosolic ribosomes, and are imported through the TOM ( T ranslocase of the O uter M embrane) apparatus; Tom40 is the central pore of this apparatus, the gateway for protein entrance into the mitochondrion (reviewed in[27]).…”

Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1

“…Thus, abnormal mitochondrial dynamics and excessive mitochondrial fission could lead to bioenergetics dysfunction in AD neurons. In fact, bioenergetics dysfunction, as measured by changes in oxygen consumption, respiratory coupling and glucose utilization has been observed in the mitochondria from AD and mild cognitive impairment (MCI) patients (Silva et al ., 2013) and in the mitochondria from AD mice (Yao et al ., 2009). It has also been reported that defective mitochondrial biogenesis contribute to mitochondrial abnormalities in AD could be rescued by cAMP dependent PKA/CREB activation pathway in Aβ overexpressed cells (Sheng et al ., 2012).…”

The role of mitochondrial disturbances in Alzheimer, Parkinson and Huntington diseases

“…A decrease in the protein levels of PGC-1a, NRF1 and NRF2, major regulators of mitochondrial biogenesis, was observed in hippocampal tissue from AD human subjects and APP mice [156,157], M17 cells expressing the APP Swedish mutation [158] and AD and mild cognitive impairment cybrid cell lines [159,160]. The protein levels of Tfam, a co-activator of PGC-1a, were found to be increased in AD and mild cognitive impairment cybrids, although no changes in its mRNA levels were observed [161]. Some studies performed in AD brains showed increased levels of mtDNA, electron transport chain (ETC) protein and mRNA levels [48,162] while other studies reported the opposite [163][164][165].…”