CRISPR screening of mtISR regulators in VCP-mutant cells

Mitochondria orchestrate both bioenergetic and stress-signaling functions, with the mitochondrial Integrated Stress Response (ISR) serving as a pivotal conduit for nuclear communication. Although mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), the specific mechanistic role of mitochondrial ISR activation in pathogenesis remains unresolved. Capitalizing on VCP-mutant ALS models, where compromised protein homeostasis converges with defective mitochondrial surveillance, we uncovered maladaptive mitochondrial ISR signaling. To mechanistically dissect this pathway, we employing a CRISPR/Cas9 screening strategy targeting the nuclear-encoded mitochondrial proteome, we define the molecular basis governing pathogenic mitochondrial ISR activation in VCP-mutant cells.