Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson’s Disease: What We Know so Far

Abstract

Parkinson’s disease (PD) is one of the most common progressive neurodegenerative diseases caused by the loss of dopamine-producing neuronal cells in the region of substantia nigra pars compacta of the brain. During biological aging, neuronal cells slowly undergo degeneration, but the rate of cell death increases tremendously under some pathological conditions, leading to irreversible neurodegenerative diseases. By the time symptoms of PD usually appear, more than 50 to 60% of neuronal cells have already been destroyed. PD symptoms often start with tremors, followed by slow movement, stiffness, and postural imbalance. The etiology of PD is still unknown; however, besides genetics, several factors contribute to neurodegenerative disease, including exposure to pesticides, environmental chemicals, solvents, and heavy metals. Postmortem brain tissues of patients with PD show mitochondrial abnormalities, including dysfunction of the electron transport chain. Most chemicals present in our environment have been shown to target the mitochondria; remarkably, patients with PD show a mild deficiency in NADH dehydrogenase activity, signifying a possible link between PD and mitochondrial dysfunction. Inhibition of electron transport complexes generates free radicals that further attack the macromolecules leading to neuropathological conditions. Apart from that, oxidative stress also causes neuroinflammation-mediated neurodegeneration due to the activation of microglial cells. However, the mechanism that causes mitochondrial dysfunction, especially the electron transport chain, in the pathogenesis of PD remains unclear. This review discusses the recent updates and explains the possible mechanisms of mitochondrial toxicant-induced neuroinflammation and neurodegeneration in PD.

Small-molecules against Oxidative stress mediated Neurodegenerative diseases

“…Mitochondria were first linked to PD when abusers of the drug MPTP developed Parkinsonism due to its metabolite MPP+ blocking complex I of the mitochondrial electron-transport chain. [55][56][57] This model has been replicated in lab animals using rotenone or MPTP, both complex I inhibitors, which result in nigral degeneration and the appearance of cytoplasmic inclusions with α-synuclein and ubiquitin immunoreactivity, leading to a Parkinsonian phenotype. 58, The toxicity mechanism in these complex I inhibition models is likely related to oxidative stress.…”

Unveiling the Journey from the Gut to the Brain: Decoding Neurodegeneration–Gut Connection in Parkinson’s Disease

“…Neuronal apoptosis contributes to PD, although it is not the only driver of the progressive neurodegeneration that occurs in PD . Apoptosis in PD can be triggered by the mitochondria-mediated pathway or the cell death receptor-mediated pathway. , Apart from this, levodopa itself can form quinone free radicals via auto-oxidation and promote apoptotic cell death in dopaminergic neurons of SNpc . Large amounts of PUFAs in the membranes of neurons make them vulnerable to oxidative stress and free radical damage, which also can result in apoptosis, a key pathophysiological process in a variety of neurological illnesses .…”

Dopaminergic neuronal death via necroptosis in Parkinson's disease: A review of the literature

“…Once inside the dopaminergic cells, 6-OHDA induces cell death through oxidative stress which increases ROS production (e.g., superoxide radicals, hydroxyl radicals, hydrogen peroxide). Also, 6-OHDA accumulates in the mitochondria, where it inhibits mitochondrial complex I activity (Glinka et al, 1997;Schober, 2004). Wu et al (2015) treated PC12 cells with 6-OHDA and analysed cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signalling proteins.…”

“…One of the critical factors in the selective degeneration of dopaminergic neurons in PD may be the association between necrosome signalling and mitochondrial dysfunction (Marshall & Baines, 2014; Sivagurunathan et al, 2023). Mitochondrial dysfunction is mainly characterized by the generation of reactive oxygen species (ROS), a decrease in mitochondrial complex I enzyme activity, cytochrome‐c release, ATP depletion and caspase 3 activation (Moon & Paek, 2015).…”