Mitochondrial UPR (mtUPR)

The mitochondrial unfolded protein response (mtUPR) is a stress-signaling pathway inside your mitochondria. It fires when misfolded or clumped proteins overwhelm the mitochondrial chaperones (folding helpers like HSP60 and HSP70, plus a protease called ClpP). In the worm C. elegans, mtUPR runs through a transcription factor (ATFS-1). Under stress, ATFS-1 heads to the nucleus instead of into the mitochondria. In mammals, the matching pathway uses ATF5, along with ATF4 and CHOP. When the mtUPR switches on, it ramps up mitochondrial chaperones, proteases, and metabolic genes to restore order in the organelle. Triggering it, with NAD+ precursors or mild mitochondrial stress, has been linked to longer life in lab organisms. But whether that carries over to mammals is not fully established.

Last reviewed: June 22, 2026

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