Rat Group IIA Secreted Phospholipase A2 Binds to Cytochrome c Oxidase and Inhibits Its Activity: A Possible Episode in the Development of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD), a progressive form of dementia, is characterized by the increased expression of secreted phospholipase A2 group IIA (GIIA) in the affected tissue and the dysfunction of neuronal mitochondria, similar to that induced by an orthologous GIIA from snake venom, β-neurotoxic ammodytoxin (Atx), in the motor neurons. To advance our knowledge about the role of GIIA in AD, we studied the effect of rat GIIA on the neuronal mitochondria and compared it with that of the Atx. We produced recombinant rat GIIA (rGIIA) and its enzymatically inactive mutant, rGIIA(D49S), and demonstrated that they interact with the subunit II of cytochrome c oxidase (CCOX-II) as Atx. rGIIA and rGIIA(D49S) bound to this essential constituent of the respiratory chain complex with an approximately 100-fold lower affinity than Atx; nevertheless, both rGIIA molecules potently inhibited the CCOX activity in the isolated rat mitochondria. Like Atx, rGIIA was able to reach the mitochondria in the PC12 cells from the extracellular space, independent of its enzymatic activity. Consistently, the inhibition of the CCOX activity in the intact PC12 cells and in the rat’s brain tissue sections was clearly demonstrated using rGIIA(D49S). Our results show that the effects of mammalian and snake venom β-neurotoxic GIIA on the neuronal mitochondria have similar molecular backgrounds. They suggest that the elevated extracellular concentration of GIIA in the AD tissue drives the translocation of this enzyme into local neurons and their mitochondria to inhibit the activity of the CCOX in the respiratory chain. Consequently, the process of oxidative phosphorylation in the neurons is attenuated, eventually leading to their degeneration. Atx was thus revealed as a valuable molecular tool for further investigations of the role of GIIA in AD.

An agonist of CXCR4 induces a rapid recovery from the neurotoxic effects of Vipera ammodytes and Vipera aspis venoms

“…The major neurotoxic snake venom components are presynaptically acting neurotoxic secreted phospholipases A 2 (sPLA2) (Kini, 2003; Rigoni et al, 2005; Rossetto et al, 2006), including the ammodytoxins (Atx) present in the V. ammodytes and V. aspis venoms (Giribaldi et al, 2020; Križaj, 2011; Latinović et al, 2016). These neurotoxic sPLA2 induce degeneration of motor neuron terminals (Cull‐Candy et al, 1976; Dixon & Harris, 1999; Logonder et al, 2008; Prasarnpun et al, 2004) via molecular mechanisms that have been recently clarified (Duregotti et al, 2013; Ivanušec, Šribar, Leonardi, et al, 2022; Ivanušec, Šribar, Veranič, & Križaj, 2022; Lomonte & Križaj, 2021; Paoli et al, 2009; Rigoni et al, 2005, 2007, 2008; Šribar et al, 2014; Tedesco et al, 2009). Accordingly, Varespladib, a specific sPLA2 inhibitor, has been recently identified and tested against different neurotoxic snake venoms with promising results (Gutiérrez et al, 2020; Lewin et al, 2022; Salvador et al, 2019; Silva‐Carvalho et al, 2021).…”