Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases

Abstract

Mitochondria participate in essential processes in the nervous system such as energy and intermediate metabolism, calcium homeostasis, and apoptosis. Major neurodegenerative diseases are characterized pathologically by accumulation of misfolded proteins as a result of gene mutations or abnormal protein homeostasis. Misfolded proteins associate with mitochondria, forming oligomeric and fibrillary aggregates. As mitochondrial dysfunction, particularly of the oxidative phosphorylation system (OXPHOS), occurs in neurodegeneration, it is postulated that such defects are caused by the accumulation of misfolded proteins. However, this hypothesis and the pathological role of proteinopathies in mitochondria remain elusive. In this study, we critically review the proposed mechanisms whereby exemplary misfolded proteins associate with mitochondria and their consequences on OXPHOS.

Figure 1.

Schematic illustration of the proposed interactions of Aβ with mitochondrial components and their effects on OXPHOS function. Amyloid precursor protein (APP) and its secretase complex processing product, Aβ, can enter mitochondria through the mitochondrial import pore complexes, represented in this figure in a simplified form by TOM40 and TIM23. Proposed interactors of Aβ and Aβ oligomers are depicted on the electron transport chain (Complexes I–V) and on the outer mitochondrial surface. PreP and ABAD are Aβ oligomer targets that have been described in the matrix.

Figure 2.

Schematic illustration of the proposed interactions of α-syn with mitochondrial components and their effects on OXPHOS function. α-Synuclein monomers and oligomers can affect mitochondrial import complexes and various components of the electron transport chain complexes. It is proposed that α-syn affects IM integrity through its interaction with cardiolipin (CL). α-Syn also affects mitochondrial and ER contact regions by interfering with the VAPB-PTPIP51 tethering complex. Mutant α-syn can disrupt MAMs. PTPIP51, protein tyrosine phosphate–interacting protein 51; VAPB, VAMP-associated protein B, an ER resident protein.

Figure 3.

Schematic illustration of the proposed interactions of SOD1 with mitochondrial components and their effects on OXPHOS function. SOD1 localizes to mitochondria, where it provides dismutase activity in the IMS. SOD1 is imported to the IMS via the Mia40-Erv1 disulfide relay pathway, and its maturation is facilitated by the copper chaperone for SOD1 (CCS). It is proposed that mutant misfolded SOD1 associates with various mitochondrial proteins both within the IMS and at the OM. Misfolded SOD1 interferes with the mitochondrial protein import machinery, ER–mitochondrial contacts, and VDAC. Among the electron transfer chain (ETC) complexes, mutant SOD1 mostly inhibits complex IV activity.