Role of mitochondrial quality control in neurodegenerative disease progression

Abstract

Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondrial quality control.

FIGURE 1

Schematic diagram of the mitochondrial structure. Figure was created with BioRender software.

FIGURE 2

Schematic illustration of the mitochondrial biogenesis. PGC-1α serves as the primary modulator of mitochondrial biogenesis, with SIRT1 and AMPK facilitating its activation through deacetylation and phosphorylation, respectively. This activation enhances the expression and functionality of TFAM by stimulating the activity of PPARs, NRF1, NRF2, and ERR-α. Subsequently, TFAM binds to the promoter region of mitochondrial subunits, thereby promoting the replication and transcription of mitochondrial mtDNA. Figure was created with BioRender software.

FIGURE 3

Schematic illustration of the mitophagy. Mitochondrial phagocytosis is facilitated by a complex interplay of mechanisms, primarily categorized into ubiquitin (Ub)-dependent and Ub-independent pathways. The Ub-dependent pathway is predominantly mediated by the PINK1/Parkin axis. Furthermore, a distinct set of mitophagy receptors is capable of directly interacting with LC3, obviating the need for extensive ubiquitination and thereby contributing to the Ub-independent pathway. The receptor proteins involved in mitochondrial autophagy include BNIP3L/NIX, FUNDC1, FKBP8PHB2, and AMBRA1, among others. Figure was created with BioRender software.

FIGURE 4

Schematic illustration of the mechanism of mitochondrial dynamics. (A) Mitochondrial fusion is governed by a set of membrane-anchored proteins, such as Mfn1, Mfn2, and Opa1. Mfn1 and Mfn2 facilitate the fusion of the outer mitochondrial membrane, while Opa1, the predominant mitochondrial DNA (mtDNA) in mammals, is responsible for the fusion of the inner mitochondrial membrane and the reshaping of mitochondrial cristae. (B) During mitochondrial division, Drp1 binds to its receptors (MFF, MID49, MID51, and FIS1) to form Drp1 oligomers, contracting the mitochondria to facilitate division. Figure was created with BioRender software.

FIGURE 5

Schematic illustration of abnormal mitochondrial quality control in neurodegenerative diseases. Figure was created with BioRender software.