A novel role for the mitochondrial HTRA2/OMI protease in aging

HTRA2/OMI is an ATP-independent serine protease located in the intermembrane space of the mitochondria and is thought to function as a protein quality control protease. Our previous studies showed that loss of the enzymatic activity of HTRA2 due to a Ser276Cys missense mutation in its catalytic domain is associated with early onset neurodegeneration, multiple tissue atrophy and premature lethality in homozygous htra2 (mnd2) mice, suggesting that HTRA2 is neuroprotective. To further investigate the role of HTRA2 in neuronal cell survival and the impact of its loss of function in non-neuronal tissues of adult mice, we generated transgenic htra2 (mnd2) mice expressing a neuron-targeted human HTRA2 transgene. Notably, this HTRA2 transgene rescues htra2 (mnd2) mice from early onset neurodegeneration, and other phenotypic abnormalities and prevents their early death, indicating that HTRA2 activity in neuronal mitochondria is important for neuronal cell survival. However, as the rescued htra2 (mnd2) mice grow older they exhibit specific phenotypic abnormalities indicative of premature aging. These include premature weight loss, osteoporosis, lordokyphosis, muscle atrophy, heart enlargement, increased autophagy and reduced life span. There is also a significant increase in the levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our findings suggest that HTRA2-regulated protein quality control in the intermembrane space of mitochondria is important for the maintenance of mitochondrial homeostasis, and loss of HTRA2 activity can lead to both neurodegeneration and aging.