Mitochondrial dysfunction is a key modulator of the ageing process. Abnormal mitochondria accumulate during ageing and their efficient elimination enhances lifespan and stress response in Caenorhabditis elegans. The actual mechanism through which mitochondrial biogenesis and function affects lifespan is currently under intensive investigation. Mitochondrial biogenesis is coordinated at distinct points; a) the transcriptional level, through the action of specific transcription factors, b) the organellar level, where conserved mitochondrial protein import translocases assist targeting of nuclear encoded mitochondrial proteins to their final destination within the organelle, and c) the quality control level, where the mitochondrial pool is maintained through fusion/fission events and autophagic elimination of damaged mitochondria. We are investigating the cause-and-effect relationships between mitochondrial protein import machineries and lifespan in the nematode. Specifically, we targeted translocase complex core subunits that transport preproteins to the mitochondrial matrix, inner and outer mitochondrial membrane, namely
timm-23 (F15D3.7),
timm-22 (C47G2.3) and
gop-3 (C34E10.1) respectively, as well as the general import pore channel-forming subunit,
tomm-40 (C18E9.6). We find that depletion of TOMM-40 and TIMM-23 induces a marked UPRmt response and promotes longevity by almost 30%. The UPRmt-linked transcription factor ATFS-1 is required for lifespan extension upon
tomm-40 and
timm-23 knockdown. We find that these effects are linked to fat metabolism regulation via the nuclear hormone receptor
nhr-49.