Mitochondrial Dysfunction in Rabies Virus-Infected Human and Canine Brains

Area of Science:

• Neuroscience
• Virology
• Cell Biology

Background:

• Rabies, a fatal encephalitis caused by Rabies lyssavirus (RABV), is characterized by minimal neuropathological changes, suggesting neuronal dysfunction rather than death.
• Previous studies on mitochondrial dysfunction in rabies relied on experimental models; studies using naturally infected host tissues were lacking.
• Mitochondrial changes are hypothesized to be a key mechanism underlying neuronal dysfunction in rabies.

Purpose of the Study:

• To investigate the role of mitochondrial alterations in rabies pathogenesis using naturally infected human and canine brain tissues.
• To analyze morphological, biochemical, and proteomic changes in mitochondria during RABV infection.

Main Methods:

• Morphological, biochemical, and proteomic analyses were performed on brain tissues from naturally RABV-infected humans and canines.
• Mitochondrial structure, protein expression related to oxidative phosphorylation and autophagy, and enzyme activities were assessed.
• Cellular assays were used to evaluate mitochondrial membrane potential in RABV-infected cells.

Main Results:

• Morphological analysis revealed preserved neurons but disrupted mitochondrial structures with minimal inflammation in infected brains.
• Proteomic analysis indicated altered mitochondrial processes (oxidative phosphorylation, homeostasis, transport), synaptic proteins, and autophagic pathways, with overexpression of mitochondrial respiratory complex subunits.
• Elevated activities of mitochondrial complexes I, IV, and V were observed, but without increased ATP production, linked to reduced mitochondrial membrane potential, mitophagy markers (PINK1, FKBP8), and autophagy markers (LC3-II, LAMP1).

Conclusions:

• Altered mitochondrial bioenergetics and cristae architecture in RABV infection likely trigger mitophagy and subsequent autophagy.
• These mitochondrial and autophagic dysfunctions contribute to neuronal dysfunction, leading to the fatal outcome of rabies.
• This study provides crucial insights into the molecular mechanisms of rabies pathogenesis directly from naturally infected host tissues.