Mitochondrial protein (MP) dysfunction has been linked to neurodegenerative disorders (NDs), however, the discovery of molecular mechanisms underlying NDs has been impeded by the limited characterization of interactions governing MP function. Here, using 109 affinity-purified mitochondrial fractions isolated from 13 epitope-tagged human ND-linked MPs in HEK293 cells coupled with mass spectrometry (MS), we report a high-confidence MP network involving 1,964 interactions among 772 proteins (>90% previously unreported). Nearly half of these interactions were confirmed in differentiated neuronal cells by primary antibody immunoprecipitation and MS, with many linked to NDs and autism. We show that the SOD1-PRDX5 interaction, critical for mitochondrial redox homeostasis, can be perturbed by amyotrophic lateral sclerosis-linked variants, and establish a new functional role for ND-linked factors coupled with IκBε in NF-kB activation. Our results identify new mechanisms for MPs with direct consequences for human disease, and expands the interaction landscape of human mitochondria