Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress

TY - JOUR

T1 - Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress

AU - Ehses, Kenneth

AU - López-Alonso, Jorge P.

AU - Antico, Odetta

AU - Lang, Yannik

AU - Rudack, Till

AU - Azem, Abdussalam

AU - Muqit, Miratul M.K.

AU - Ubarretxena-Belandia, Iban

AU - Fernández-Busnadiego, Rubén

N1 - Publisher Copyright: © 2026 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2026/3/4

Y1 - 2026/3/4

N2 - Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo–electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo–electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.

AB - Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo–electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo–electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.

UR - https://www.scopus.com/pages/publications/105032173683

U2 - 10.1126/sciadv.aed3579

DO - 10.1126/sciadv.aed3579

M3 - Article

C2 - 41779846

AN - SCOPUS:105032173683

SN - 2375-2548

VL - 12

SP - 1

EP - 20

JO - Science Advances

JF - Science Advances

IS - 10

ER -