Mitochondrial Dysfunction and Renal Tubular Injury in Malignancy-Associated Hypercalcemia; a Mechanistic Framework for Acute Kidney Injury in Advanced Renal Cancer

Malignancy-associated hypercalcemia represents a severe metabolic complication frequently observed in advanced renal cell carcinoma (RCC), often precipitating acute kidney injury (AKT) and limiting therapeutic options. Though systemic volume depletion and renal vasoconstriction contribute to renal disturbance, direct tubular toxicity mediated by intrinsic mitochondrial dysfunction remains underexplored. This review discusses on mechanistic framework linking excessive extracellular calcium load to renal tubular epithelial failure. Hypercalcemia induces profound intracellular calcium overload within proximal tubular cells, triggering mitochondrial calcium uniporter activation. Consequently, mitochondrial membrane potential collapses due to permeability transition pore opening, effectively uncoupling oxidative phosphorylation. This bioenergetic crisis generates excessive reactive oxygen species (ROS), promoting lipid peroxidation, protein oxidation and DNA damage. Simultaneously, cytochrome c release initiates apoptotic cascades, whereas severe ATP depletion triggers necrotic cell death. The resulting tubular obstruction, cast formation, and inflammation exacerbate glomerular filtration rate loss. Furthermore, tumor-derived factors like parathyroid hormone-related protein (PTHrP) may sensitize mitochondria to calcium-induced stress, amplifying injury. Dysregulated mitochondrial dynamics, including fission and fusion imbalance, further compromise cellular resilience against calcium stress. Identification this pathway highlights mitochondria as critical therapeutic targets beyond standard hydration and bisphosphonates. Interventions stabilizing mitochondrial integrity, modulating calcium handling, or scavenging ROS could mitigate tubular injury. Eventually, deciphering these molecular events offers novel strategies to preserve renal function in patients with advanced renal cancer suffering from hypercalcemic crises. Such approaches may significantly improve survival outcomes and enable continued systemic therapy, addressing a critical unmet need in oncology nephrology where renal preservation dictates treatment eligibility and quality of life during palliative care.