The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

Abstract

Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE) experiments in p66Shc knockout mice (p66Shc−/−), knock out mice for cyclophilin-D (Cyc-D−/−), and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/−) mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts

“…In fact, several studies performed in p66Shc −/− cells show a decrease in intracellular ROS (Savino et al 2013;Trinei et al 2002), possibly explaining the observed protection against aging-associated diseases.…”

The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

“…When CyPD-null mice are treated, they display a marked protection from axonal degeneration and a milder clinical picture despite a normal inflammatory response, thus providing strong evidence that PTP is involved in disease pathogenesis (193). A further indication of the central role played by the PTP in multiple sclerosis is provided by the observation that axonal damage of mice undergoing experimental autoimmune encephalomyelitis is reduced by genetic inactivation of p66Shc, which abrogates an important pathway of ROS-induced PTP opening (see above) (514).…”

Mitochondrial Ca2+ and regulation of the permeability transition pore

“…In clinical trials, treatment with CsA at reperfusion reduced levels of the biomarkers troponin and mitochondrial creatine kinase (mtCK) and reduced total infarct size (Piot et al 2008). In many neurological disorders dysregulated Ca 2+ and ROS levels appear to have some component of injury mediated by increased mPTP opening, including excitotoxicity (Pivovarova and Andrews 2010), epilepsy (Jung et al 2012), Huntington’s disease (Quintanilla et al 2013), Alzheimer’s disease (Du et al 2011), Parkinson’s disease (Martin et al 2014b), Amyotrophic Lateral Sclerosis (Martin et al 2014a), and Multiple Sclerosis (Savino et al 2013). Conversely, it appears that susceptibility to mPTP opening is reduced in cancer, leading to cell resilience.…”