Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase

Abstract

Summary Loss of noradrenergic locus coeruleus (LC) neurons is a prominent feature of aging–related neurodegenerative diseases, like Parkinson’s disease (PD). The basis of this vulnerability is not understood. To explore possible physiological determinants, LC neurons were studied using electrophysiological and optical approaches in ex vivo mouse brain slices. These studies revealed that autonomous activity in LC neurons was accompanied by oscillations in dendritic Ca2+ concentration attributable to opening of L–type Ca2+ channels. This oscillation elevated mitochondrial oxidant stress and was attenuated by inhibition of nitric oxide synthase. The relationship between activity and stress was malleable, as arousal and carbon dioxide, each increased the spike rate, but differentially affected mitochondrial oxidant stress. Oxidant stress also was increased in an animal model of PD. Thus, our results point to activity–dependent Ca2+ entry and a resulting mitochondrial oxidant stress as factors contributing to the vulnerability of LC neurons.

Redox imaging using genetically encoded redox indicators in zebrafish and mice

“…Notably, mutations in the DJ-1 gene are responsible for a familial form of PD. Similar effects of calcium currents on mitochondrial oxidation were recently identified in other dopaminergic circuits (Goldberg et al, 2012;Sanchez-Padilla et al, 2014) affected in PD.…”

The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain

“…One factor is their high bioenergetic need. Perhaps as part of mechanisms that insure maintained operation during essential physiological functions, LC neurons maintain their spiking rate even when glutamate and GABA inputs are blocked [98]. L-type Ca 2+ channels enhance the reliability of this autonomous spiking, but at the cost of increased mitochondrial oxidant stress [98].…”

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

“…For example, VTA DA neurons, which are significantly less vulnerable than SNc DA neurons (see above), are autonomous pacemakers with broad spikes, but have smaller Cav1 channel currents and strong intrinsic Ca 2+ buffering (Guzman et al, 2009; Khaliq et al, 2010). Although there have been very few studies that have examined these features in other at-risk neurons, those that have (LC, DMV, PPN) show that this phenotype is largely shared (Goldberg et al, 2012; Kang and Kitai, 1990; Sánchez-Padilla et al, 2014). …”

“…Ca1.3 channels, because they activate at sub-threshold membrane potentials, are critical to this function (Guzman et al, 2009; Helton et al, 2005; Puopolo et al, 2007). Second, although less well established, they promote Ca 2+ entry into mitochondria, oxidative phosphorylation (OXPHOS) and the production of ATP (Guzman et al, 2010; Llorente-Folch et al, 2015; Sánchez-Padilla et al, 2014). In principle, this feed-forward control of OXPHOS helps to ensure that bioenergetic needs are met (Balaban, 2009; Nicholls, 1998) and that intracellular ATP levels do not fall into a range that would trigger protective activation of K-ATP channels and cessation of on-going activity (Dragicevic et al, 2015).…”

“…First, stimulating OXPHOS when mitochondria are hyperpolarized in the absence of strong ATP demand increases the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Goldberg et al, 2012; Guzman et al, 2010; Sánchez-Padilla et al, 2014; Votyakova and Reynolds, 2001). ROS and RNS damage proteins, lipids and DNA, particularly in mitochondria.…”