Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?

Abstract

Neurodegenerative diseases encompass a spectrum of conditions characterized by the gradual deterioration of neurons in the central and peripheral nervous system. While their origins are multifaceted, emerging data underscore the pivotal role of impaired mitochondrial functions and endolysosomal homeostasis to the onset and progression of pathology. This article explores whether mitochondrial dysfunctions act as causal factors or are intricately linked to the decline in endolysosomal function. As research delves deeper into the genetics of neurodegenerative diseases, an increasing number of risk loci and genes associated with the regulation of endolysosomal and autophagy functions are being identified, arguing for a downstream impact on mitochondrial health. Our hypothesis centers on the notion that disturbances in endolysosomal processes may propagate to other organelles, including mitochondria, through disrupted inter-organellar communication. We discuss these views in the context of major neurodegenerative diseases including Alzheimer's and Parkinson's diseases, and their relevance to potential therapeutic avenues.

Keywords: lysosomal homeostasis; mitochondrial homeostasis; neurodegenerative diseases.

FIGURE 1

Mitochondrial DNA (mtDNA) structure and schematic representation of the electron transport chain. A small amount of the genetic data required for mitochondrial function is encoded on the mitochondrial chromosome, also called mtDNA (mitochondrial DNA). It contains genes required for production of proteins involved in oxidative phosphorylation and other mitochondrial processes. Protein‐coding genes encode various proteins involved in mitochondrial function, such as components of the electron transport chain, including subunits of cytochrome c oxidase (COX) and ATP synthase (ATPase; colors match between genes and proteins). Ribosomal RNA (rRNA) genes encode the rRNA molecules that are essential components of the mitochondrial ribosomes. They are involved in protein synthesis within the mitochondria. Thirdly, transfer RNA (tRNA) genes encode tRNA molecules, which are responsible for linking specific amino acids to the growing polypeptide chain during protein synthesis. Mitochondrial tRNAs are required for the translation of mitochondrial‐encoded proteins. Lastly, some non‐coding regions encompass regulatory elements including the control region or D‐loop. This region plays a role in the regulation of replication and transcription of mtDNA. It is important to note that the majority of the genes required for mitochondrial function are actually encoded by nuclear DNA (nDNA) and not on the mitochondrial chromosome itself.

FIGURE 2

The principal mechanisms of mitophagy. These include (I) lipid‐mediated mitophagy, mainly initiated by cardiolipin transfer from the inner mitochondrial membrane (MM) during the process of mitophagy (II) In receptor‐mediated mitophagy, outer MM receptors such as FKBP8 bind directly to LC3s, allowing for the formation of a mitophagosome (III) Lastly, ubiquitin‐mediated mitophagy consists of two pathways: PINK1‐Parkin‐dependent mitophagy and Parkin‐independent mitophagy. During PINK1‐Parkin‐dependent mitophagy, PINK1 accumulates on the outer MM and recruits Parkin from the cytosol to the outer MM. This leads to the phosphorylation and ubiquitination of proteins on the outer MM, ultimately resulting in the formation of the mitophagosome. In Parkin‐independent mitophagy, other E3 ubiquitin ligases like MUL1, are at play.

FIGURE 3

The interplay between lysosomal function and mitochondrial health. The top panel depicts a healthy cellular state in which lysosomes efficiently degrade cellular waste and damaged mitochondria via autophagy. The mitochondria, through the TCA cycle, generate ATP and provide essential metabolites for lipid and cholesterol synthesis, as well as other cellular processes. In case of a lysosomal catabolic bottleneck (bottom panel), compromised lysosomal activity results in a hindering of the autophagic flux and the accumulation of damaged mitochondria. Similarly to lysosomes, leaky mitochondria release free cytosolic DNA, which activates the cGAS‐STING pathway, leading to type I interferon responses (IRF3) and inflammation. In parallel, this cascade of events results in reduced energy supply, NAD+ depletion, and increased reactive oxygen species (ROS) damage, further exacerbating lysosomal dysfunction. The interactions between affected mitochondria and lysosomes illustrate the bidirectional relationship where impaired lysosomal function hinders the removal of defective mitochondria, and vice versa, highlighting the critical need for maintaining the integrity of both organelles for cellular health.

FIGURE 4

Lyso‐Mito Membrane Contact Sites (MCSs). The schematic representation of molecular interactions at MCSs between lysosomes and mitochondria. Key components involve TRPML1, a lysosomal cation channel responsible for Ca²⁺ transfer to mitochondria, and VDAC1, a mitochondrial channel. Cholesterol and iron are also exchanged at these sites. Other important proteins such as LAMP1, RAB7, GDAP1, and VPS13A play crucial roles in maintaining the structural and functional integrity of these contacts, ensuring efficient lipid and ion transfer necessary for cellular homeostasis. The electron microscopy image on the right showcases the physical proximity of lysosomes (Lys) and mitochondria (Mito) within the cell. The arrows indicate the close contact points, highlighting the regions where inter‐organellar communication occurs. The scale bar represents 500 nm.