Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment

• MQC dysfunction is a central, unifying mechanism in chemotherapy-related cognitive impairment (CRCI). • Diverse chemotherapeutics disrupt all five MQC pillars: biogenesis, mitophagy, dynamics, proteostasis, and MDVs. • Agent-specific MQC vulnerabilities drive neuroinflammation, BBB disruption, synaptic loss, and cognitive deficits. • Mitochondria-targeted interventions offer a robust framework for CRCI neuroprotection without anticancer efficacy compromise. Chemotherapy-related cognitive impairment (CRCI), colloquially termed “chemobrain,” remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.