LONP1 de novo dominant mutation causes mitochondrial encephalopathy with loss of LONP1 chaperone activity and excessive LONP1 proteolytic activity.

LONP1 is an ATP-dependent protease and chaperone that plays multiple vital roles in mitochondria. LONP1 is essential for mitochondrial homeostasis due to its role in maintenance of the mitochondrial genome and its central role in regulating mitochondrial processes such as oxidative phosphorylation, mitophagy, and heme biosynthesis. Bi-allelic LONP1 mutations have been reported to cause a constellation of clinical presentations. We report a patient heterozygous for a de novo mutation in LONP1: c.901C>T,p.R301W presenting as a neonate with seizures, encephalopathy, pachygyria and microcephaly. Assays of respiratory chain activity in muscle showed complex II-III function at 8% of control. Functional studies in patient fibroblasts showed a signature of dysfunction that included significant decreases in known proteolytic targets of LONP1 (TFAM, PINK1, phospho-PDH E1α) as well as loss of mitochondrial ribosome subunits MRPL44 and MRPL11 with concomitant decreased activity and level of protein subunits of oxidative phosphorylation complexes I and IV. These results indicate excessive LONP1 proteolytic activity and a loss of LONP1 chaperone activity. Further, we demonstrate that the LONP1 N-terminal domain is involved in hexamer stability of LONP1 and that the ability to make conformational changes is necessary for LONP1 to regulate proper functioning of both its proteolytic and chaperone activities.