Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility

Herpes simplex virus 1 (HSV-1) is a common infection affecting around 67% of the global population. It resides in sensory neurons for life and has been associated with various issues, including neuronal dysfunction. One notable effect of HSV-1 infection is the disruption of mitochondrial homeostasis, but the exact mechanisms behind these changes remain unclear.

The virus targets mitochondrial DNA and transcription factors, resulting in reduced mitochondrial biogenesis, which is essential for energy production. However, the virus employs additional strategies to counteract these effects, ensuring its survival and replication.

HSV-1 infection leads to an inhibition of mitochondrial fusion, causing the mitochondria to cluster around the nucleus. This results in a smaller network, providing the virus with a localized energy source and facilitating its envelopment. Furthermore, the virus downregulates the outer mitochondrial membrane fusion protein, MFN2, exacerbating the fragmented mitochondrial network.

Another key player affected is the inner mitochondrial membrane protein, TIM23, which also experiences downmodulation during infection. These modifications allow the virus to evade certain cellular defensive mechanisms, including mitophagy, which normally eliminates damaged mitochondria.

Interestingly, despite these alterations to mitochondrial function, the virus manages to protect mitochondria from mitophagy. It achieves this by degrading proteins involved in the mitophagy process, allowing damaged mitochondrial components to be expelled through extracellular vesicles. Even with these mitochondrial changes, essential functions required for HSV-1 infection, such as basal cell respiration, are maintained.

Additionally, the virus increases spare respiratory capacity and extracellular acidification rates, indicating heightened glycolytic activity. Importantly, the virus also preserves the mitochondrial membrane potential, ensuring efficient cellular function despite the overall changes in mitochondrial organization and function.

This research sheds light on the complex ways HSV-1 manipulates mitochondria, offering valuable insights into the virus's pathogenic mechanisms. Understanding these processes could potentially lead to new strategies for managing or combating HSV-1-associated diseases.