Comparison of the structure, function and autophagic maintenance of mitochondria in nigrostriatal and tuberoinfundibular dopamine neurons

Abstract

A pathological hallmark of Parkinson disease (PD) is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, which underlies the motor symptoms of PD. While there is severe loss of midbrain NSDA neurons, tuberoinfundibular (TI) DA neurons in the mediobasal hypothalamus (MBH) remain intact. In the present study, confocal microscopic analysis revealed that mitochondrial content and numbers of mitophagosomes were lower in NSDA neuronal cell bodies in the substantia nigra pars compacta (SNpc) compared to TIDA neuronal cell bodies in the arcuate nucleus (ARC) of C57BL/6J male mice. Mitochondrial respiration, mass, membrane potential and morphology were determined using bioenergetic, flow cytometric and transmission electron microscopic analyses of synaptosomes isolated from discrete brain regions containing axon terminals of NSDA and TIDA neurons. Maximum and spare respiratory capacities, and mitochondrial mass were lower in synaptosomal mitochondria derived from the striatum (ST) as compared with the MBH, which correlated with lower numbers of mitochondria per synaptosome in these brain regions. In contrast, there was no regional difference in mitochondrial basal, maximum or spare respirations following inhibition of Complex I activity with rotenone. These results reveal that higher numbers of viable mitochondria are correlated with more extensive autophagic mitochondrial quality maintenance in TIDA neurons as compared with NSDA neurons.

Aldehyde Dehydrogenase 2 Protects Against Post-Cardiac Arrest Myocardial Dysfunction Through a Novel Mechanism of Suppressing Mitochondrial Reactive Oxygen Species Production

“…Thin sections (70 nm) of left ventricular tissue were stained and examined using a scanning TEM (JEOL Ltd., Tokyo, Japan) (Huang et al, 2011). The severity of mitochondrial structural damage was semi-quantified using Flameng grading of 1 through 5 as described previously (Flameng et al, 1980;Hawong et al, 2015).…”

Ghrelin mediated neuroprotection - A possible therapy for Parkinson's disease?

“…The underlying cause of PD is unknown, however, mitochondrial dysfunction and/or damage is thought to contribute to its pathophysiology (Abou-Sleiman et al, 2006;Hawong, Patterson, Winner, Goudreau, & Lookingland, 2015;Kitada et al, 1998;Schapira et al, 1989;Sorrentino et al, 2017). Mitochondrial malfunction can lead to reduced mitochondrial biogenesis (St-Pierre et al, 2006), increased synthesis of free radicals and oxidative stress (Lin & Beal, 2006;Perfeito, Ribeiro, & Rego, 2016;St-Pierre et al, 2006), decreased production of ATP (Mann et al, 1992), build-up of H + ions due to reduced mitochondrial uncoupling (Andrews et al, 2009;Conti et al, 2005)…”

Less is more: Caloric regulation of neurogenesis and adult brain function

“…Sustaining the presence of healthy mitochondria may attenuate the decrease in age and disease‐related brain function. Indeed, the increased presence of abnormal “donut” shaped mitochondria has been linked to decreased age‐related cognitive function in monkeys and mitochondrial damage is likely to contribute to the pathophysiology of AD, PD and HD . Furthermore, several proteins linked to mitochondrial function are mutated in familial forms of PD, including α‐synuclein, PTEN‐induced putative kinase 1 (PINK1), parkin, LRRK2, protein deglycase DJ‐1 and high temperature requirement protein A2 (HTRA2) .…”

“…ATG, autophagy-related; LRRK2, leucine-rich repeat kinase 2 Indeed, the increased presence of abnormal "donut" shaped mitochondria has been linked to decreased age-related cognitive function in monkeys 59 and mitochondrial damage is likely to contribute to the pathophysiology of AD, PD and HD. [60][61][62][63][64][65] Furthermore, several proteins linked to mitochondrial function are mutated in familial forms of PD, including α-synuclein, PTEN-induced putative kinase 1 (PINK1), parkin, LRRK2, protein deglycase DJ-1 and high temperature requirement protein A2 (HTRA2). 66 Together, these studies suggest damage to multiple elements of the mitochondria, including proteins, lipids, DNA and extra-mitochondrial structures.…”