Exploring Mitochondrial Regulatory Pathways and Apoptotic Signaling as Host-Directed Targets for Broad-Spectrum Antivirals

Current direct antiviral strategies that target viral factors offer limited long-term broad-spectrum potential against emerging and re-emerging viruses. In contrast, many viruses rely on conserved host cellular machinery to complete their life cycles, making host-directed strategies a promising avenue for broad-spectrum therapeutics. Among host organelles, mitochondria play central roles in metabolism, innate immune signaling, and programmed cell death. Increasing evidence suggests that diverse viral families interact with mitochondrial regulatory pathways, but the broad-spectrum antiviral potential of these still remains largely unexplored. Mitochondrial regulatory pathways include dynamic processes such as fusion, fission, mitophagy, and antiviral signaling networks. Many of these are targeted by viruses in diverse and often opposing ways. However, the mitochondrial apoptotic pathway appears to represent a consistent point of viral convergence and therefore holds strong potential as a host-directed target. To evaluate its potential, the article examines how WHO-prioritized viral pathogens interact with mitochondrial apoptotic pathways throughout their life cycles and whether modulation of key apoptotic regulators represents a feasible, low-toxicity broad-spectrum antiviral strategy. Findings suggest that viruses consistently converge on the mitochondrial apoptotic pathway, although mechanisms of modulation vary across stages of the viral life cycle. MAVS and BCL-2 emerge as central nodes of interaction: MAVS is targeted for downregulation through various mechanisms, whereas BCL-2 exhibits bidirectional, context-dependent modulation. While this convergence supports mitochondrial apoptosis as a shared interface of host–virus interaction, variability in mechanism and timing limits its therapeutic exploitability. Despite these constraints, mitochondrial apoptotic signaling remains a promising, underexplored avenue for broad-spectrum antiviral development.