p66Shc activation promotes increased oxidative phosphorylation and renders CNS cells more vulnerable to amyloid beta toxicity

Abstract

A key pathological feature of Alzheimer’s disease (AD) is the accumulation of the neurotoxic amyloid beta (Aβ) peptide within the brains of affected individuals. Previous studies have shown that neuronal cells selected for resistance to Aβ toxicity display a metabolic shift from mitochondrial-dependent oxidative phosphorylation (OXPHOS) to aerobic glycolysis to meet their energy needs. The Src homology/collagen (Shc) adaptor protein p66Shc is a key regulator of mitochondrial function, ROS production and aging. Moreover, increased expression and activation of p66Shc promotes a shift in the cellular metabolic state from aerobic glycolysis to OXPHOS in cancer cells. Here we evaluated the hypothesis that activation of p66Shc in CNS cells promotes both increased OXPHOS and enhanced sensitivity to Aβ toxicity. The effect of altered p66Shc expression on metabolic activity was assessed in rodent HT22 and B12 cell lines of neuronal and glial origin respectively. Overexpression of p66Shc repressed glycolytic enzyme expression and increased both mitochondrial electron transport chain activity and ROS levels in HT22 cells. The opposite effect was observed when endogenous p66Shc expression was knocked down in B12 cells. Moreover, p66Shc activation in both cell lines increased their sensitivity to Aβ toxicity. Our findings indicate that expression and activation of p66Shc renders CNS cells more sensitive to Aβ toxicity by promoting mitochondrial OXPHOS and ROS production while repressing aerobic glycolysis. Thus, p66Shc may represent a potential therapeutically relevant target for the treatment of AD.

Transcriptional re-programming in rat central nervous system two weeks after burn trauma: the impact of nephrilin treatment on the expression of oxidative stress-related genes

“…Several additional genes induced by burn injury and known to play key roles in mitochondrial biogenesis, function, mitophagy, fission and fusion were not affected by nephrilin treatment ( Figure 1e ): STEAP4, 38 SHC1, 39 GLUL, 40 SLC23A2, 41 PINK1 42 and MFN2. 43 Expression of ACMSD, 44 PPARGC1A 45 and FIS1 46 genes was not changed by burn injury or nephrilin treatment.…”

“…The results demonstrate that burn injury causes significant increases in the expression of all genes except OXR1, which remained unchanged, and nephrilin treatment significantly reduces transcript elevations for all remaining genes except NOX4. Several additional genes induced by burn injury and known to play key roles in mitochondrial biogenesis, function, mitophagy, fission and fusion were not affected by nephrilin treatment (Figure 1e): STEAP4, 38 SHC1, 39 GLUL, 40 SLC23A2, 41 PINK1 42 and MFN2. 43 Expression of ACMSD, 44 PPARGC1A 45 and FIS1 46 genes was not changed by burn injury or nephrilin treatment.…”

Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases

“…The decrease of energy metabolism due to defective OXPHOS causes excessive accumulation of ROS and elevated oxidative stress, which creates a transient feedback loop that further leads to mitochondrial damage (Wang et al, 2005;. Evidence indicates that CNS cells are more sensitive to Aβ-induced cytotoxicity by promoting ETC activity, mitochondrial OXPHOS, and ROS levels while repressing aerobic glycolysis (Lone et al, 2018). However, in human SH-SY5Y neuroblastoma cells, a higher level of endogenous Aβ was shown to cause no OXPHOS disturbance (Lopez Sanchez et al, 2017), suggesting that APP may downregulate mitochondrial OXPHOS independently.…”

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

“…Restricting cells to pyruvate as the sole fuel source strongly directs cellular metabolism to OXPHOS for ATP production 18 . A by-product of OXPHOS is mitochondrial ROS production 31 . While ROS are important signalling molecules, ROS build-up can cause cell death 32 .…”

“…However, the role of OXPHOS during somatic cell reprogramming is less defined. ROS are natural by-products of mitochondrial electron transport chain (ETC) activity 31 . Although ROS are important signalling molecules implicated in cell stress response and development, excess ROS is cytotoxic 32 .…”