Mitochondria are the most crucial energy-generating organelles in eukaryotic cells and serve as signaling hubs that orchestrate metabolism, redox balance, cell-fate decision and multiple forms of cell death. Mitochondria possess their own DNA (mtDNA), which is independent of the nuclear genome, yet encodes only 13 polypeptides, 22 tRNAs, and 2 rRNAs. The remaining >1 150 mitochondrial proteins are encoded by nuclear genes (nDNA), and the two genomes cooperate to preserve cellular homeostasis and proper function. Mitochondrial proteins are localized to the outer mitochondrial membrane (OMM), intermembrane space (IMS), inner mitochondrial membrane (IMM) or matrix, participating in oxidative phosphorylation (OXPHOS), the tricarboxylic acid cycle (TCA), fission-fusion dynamics, and other processes indispensable for mitochondrial integrity. Mitochondrial quality control (MQC) is exerted largely by mitochondrial proteases, which selectively modulate protein activity and degrade misfolded or superfluous proteins. Among them, a group of mitochondrial AAA+ proteases (ATPases associated with diverse cellular activities) couple ATP binding and hydrolysis to protein unfolding and proteolysis, thereby regulating fusion protein maturation, respiratory-chain assembly, and mtDNA replication/transcription. Mutations or aberrant expression of these mitochondrial AAA+ proteases cripple mitochondrial architecture and function, precipitating a spectrum of severe neurological disorders. This review summarizes current knowledge on three paradigmatic mitochondrial AAA+ proteases, LONP1, YME1L1, and AFG3L2. We highlight their conserved Walker A/B motifs in the ATPase domain and hexameric architecture, yet emphasize divergent sub-mitochondrial topologies: LONP1 is soluble in the matrix, whereas YME1L1 and AFG3L2 are embedded in the IMM with catalytic domains facing IMS and matrix, respectively. These positional differences translate into distinct substrates and proteolytic strategies, enabling a division of labor and mutual complementation that cooperatively safeguards mitochondrial proteostasis. Pathogenic mutations linked to common and rare neurological disorders are mapped predominantly to the ATPase and the hydrolase/peptidase domains. Substitutions of the amino acid within these core domains can directly abolish ATP hydrolysis, substrate engagement or peptide cleavage, thereby crippling local MQC networks. Additional variants may disturb transcriptional, translational or post-translational regulation, altering protease stoichiometry and impairing compartmental balance. The subsequent cascade, mtDNA instability, respiratory-chain dysfunction, and aberrant mitochondrial dynamics, propagates stress signals that culminate in neuronal dysfunction and/or neurodegeneration. The mutational and clinical heterogeneity observed across cell types, developmental stages, and genetic backgrounds underscores the context-dependent fine-tuning of these AAA+ proteases. Deciphering how disease-associated variants rewire domain structure, catalytic cycle, and network-level crosstalk will therefore illuminate pathophysiologic mechanisms and guide precision therapeutic strategies.