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Jacobs, L.J.* ; Doll, S. ; Trümbach, D. ; Veronese, M.* ; Di Pietro, G.* ; Yapici, F.I.* ; Hasberg, L.* ; Gentzsch, P.* ; Gerlich, S.* ; Hansen, J. ; von Karstedt, S.* ; Rugarli, E.I.* ; Conrad, M. ; Salvador, A.* ; Riemer, J.*

Cytosolic PRDX1 acts as an extramitochondrial sink to set mitochondrial H2O2 levels and enable resilience to chronic mitochondrial oxidative stress.

Redox Biol. 94:104195 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Hydrogen peroxide (H2O2) plays a dual role as both a signalling molecule and a mediator of oxidative stress. Although mitochondria are major producers of H2O2, the relative contributions of mitochondrial versus cytosolic antioxidant systems to mitochondrial H2O2 homeostasis in intact cells remain poorly defined. Here, we combined compartment-resolved live-cell imaging using HyPer7, inducible mitochondrial H2O2 generation (matrix-targeted d-amino acid oxidase), kinetic modelling, and a targeted CRISPR/Cas9 screen to dissect determinants of mitochondrial H2O2 dynamics in HEK293 cells. Unexpectedly, we found that the cytosolic peroxiredoxin PRDX1 is a dominant regulator of mitochondrial matrix H2O2 levels. Loss of cytosolic PRDXs markedly enhanced matrix Hyper7 signals under both exogenous and mitochondria-intrinsic H2O2 production, exceeding the effects of deleting mitochondrial peroxiredoxins. Modelling and transport experiments indicated a very high permeability of the mitochondrial inner membrane to H2O2 enabling rapid efflux and the establishment of steep concentration gradients. This permits the cytosol to function as a major sink to limit matrix H2O2 accumulation. PRDX1 deficiency sensitized cells to chronic mitochondrial oxidative stress. A targeted CRISPR screen identified the Rab7 GAP TBC1D5, linking mitophagy to cellular survival under these conditions. Consistently, PRDX1/2-deficient cells exhibited elevated mitophagic flux, indicating mitochondrial quality control as a compensatory response. Our study reveals that cytosolic PRDXs critically impact mitochondrial redox homeostasis and provides a systems-level framework for understanding compartmental redox control and stress adaptation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2213-2317
e-ISSN 2213-2317
Zeitschrift Redox Biology
Quellenangaben Band: 94, Heft: , Seiten: , Artikelnummer: 104195 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)