Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson’s disease

Abstract

Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of Parkinson’s disease (PD). Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. Here, we have studied the mitochondrial protein import system in in vitro and in vivo models of PD. Complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import, which was associated with a downregulation of two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23), both in vitro and in vivo. In vitro, those changes were associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Most of these pathogenic changes, including mitochondrial dysfunction and dopaminergic cell death, were abrogated by TOM20 or TIM23 overexpression, in vitro. However, in vivo, while TOM20 overexpression exacerbated neurodegeneration in both substantia nigra (SN) pars compacta (pc) and striatum, overexpression of TIM23 partially protected dopaminergic neurons in the SNpc. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to further characterize mitochondrial protein import deficit in the context of PD.

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

“…Aberrant mitochondrial regulation occurs in Parkinson's disease (Franco‐Iborra et al . ; Grunewald et al . ; Park et al .…”

MUL1 gene polymorphisms and Parkinson’s disease risk

“…15 It was believed that disruption of mitochondrial homeostasis and subsequent mitochondrial dysfunction would play a critical role in the development of neurodegenerative diseases including PD. 14,16 Generally, nerve cells clear damaged mitochondria through mitochondrial autophagy, thereby controlling the quality of the protein produced to maintain the normal function of the nerve cells. 17 When this process is not completed properly, sion, suggesting MUL1 may be a potential tumor suppressor gene.…”

“…bioenergy defects and mitochondrial dysfunction can lead to progressive decline of the central nervous system, and can even lead to endogenous apoptosis of neurons 16,18. Parkinson's disease may occur when the same pathological changes occur in dopaminergic cells in the substantia nigra.…”

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

“…Mitochondrial dysfunction is a core pathomechanism of PD (Franco-Iborra et al, 2018). This is underlined by the environmental risk factor rotenone, which inhibits the complex I of the mitochondrial electron transport chain and is epidemiologically linked to PD (Tanner et al, 2011).…”