LETM1 is an inner mitochondrial membrane protein essential for mitochondrial homeostasis and cellular viability 1. Its primary function involves regulating mitochondrial cation and volume homeostasis through dual mechanisms: mediating proton-dependent calcium efflux from mitochondria 2 and functioning as an electroneutral mitochondrial potassium/proton exchanger 3. LETM1 is crucial for maintaining mitochondrial tubular morphology, cristae organization, and respiratory chain complex assembly and stability 3. Beyond osmoregulation, LETM1 exhibits pleiotropic functions including roles in glucose utilization, mitochondrial DNA organization, and ribosome assembly 4. Bi-allelic LETM1 variants cause childhood-onset neurodegeneration with multisystem mitochondrial dysfunction 3. Clinical presentations include predominantly infantile-onset global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%), with 100% presenting respiratory chain complex deficiencies 3. Pathogenic variants impair mitochondrial K+ efflux, causing matrix swelling and loss of oxidative phosphorylation components 3. Additionally, reduced LETM1 levels in plasma neuronal extracellular vesicles correlate with major depressive disorder, normalizing with SSRI treatment response 5. LETM1 dysregulation also promotes renal cell carcinoma proliferation and metastasis through Wnt/β-Catenin signaling 6.