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

•A de novo mutation in LONP1 causes neonatal-onset encephalopathy.•Patient tissue showed excessive LONP1 proteolytic activity.•Patient tissue showed decreased LONP1 chaperone activity.•N-terminal mutation LONP1:c.901C>T,p.R301W causes increased LONP1 oligomerization.•LONP1 conformational change is essential for regulation of its activity.