bims-cemest 2025-06-01 papers

Biol Chem. 2025 May 27.

The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.

Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.

The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.

Keywords: IMS; mitochondria; protein import; proteostasis; stress responses

DOI: https://doi.org/10.1515/hsz-2025-0108

Blood. 2025 May 28. pii: blood.2024027846. [Epub ahead of print]

PERK Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation.

Manxi Zheng, Qinlu Peng, Erin M Kropp, Zhejuan Shen, Suxuan Liu, Zhengyou Yin, Sho Matono, Takao Iwawaki, Xiang Wang, Ken Inoki, Yang Mei, Qing Li, Lu Liu.

The integrity of the hematopoietic stem cell (HSC) pool depends on effective long-term self-renewal and the timely elimination of damaged or differentiation-prone HSCs. While the PERK branch of the unfolded protein response (UPR) has been shown to initiate pro-apoptotic signaling in response to ER stress in vitro, its role in regulating HSC fate in vivo remains incompletely understood. Here, we demonstrate that PERK is dispensable for steady-state hematopoiesis and HSC self-renewal under homeostatic conditions. However, under ER stress induced by disruption of ER-associated degradation (ERAD), via knockout of key components such as Sel1L or Hrd1, PERK becomes activated and drives HSC proliferation and depletion. Notably, deletion of PERK or expression of a kinase-dead PERK mutant significantly rescues the HSC defects caused by Sel1L or Hrd1 loss. Mechanistically, ERAD deficiency does not lead to increased HSC apoptosis or elevated reactive oxygen species (ROS), and PERK knockout has minimal impact on HSC apoptosis. Instead, PERK activation promotes aberrant mTOR signaling and HSC hyperproliferation, ultimately compromising self-renewal capacity. This PERK-driven elimination of stressed HSCs may function as a protective mechanism to maintain overall HSC pool integrity. Collectively, our findings reveal a previously unrecognized, proliferative, and apoptosis-independent role for PERK in regulating HSC fate under ER stress, highlighting a novel mechanism for preserving HSC homeostasis.

DOI: https://doi.org/10.1182/blood.2024027846

Autophagy. 2025 May 25.

Endoplasmic reticulum tubule junctions are sites of autophagy.

Susan Ferro-Novick.

Selective endoplasmic reticulum (ER) macroautophagy/autophagy, also called reticulophagy, is a disposal pathway that degrades ER domains. A major role of reticulophagy is the removal of ER domains that contain misfolded proteins resistant to ER-associated degradation (ERAD). Our studies have shown that RTN3L, the SEC24C-SEC23 COPII coat subcomplex, and the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L targets ERAD-resistant misfolded protein condensates for degradation at ER-reticulophagy sites (ERPHS), autophagic sites that form at tubule junctions. Unexpectedly, we found that the Parkinson disease protein PINK1 regulates ER tubulation. Loss of PINK1 disrupts the formation of peripheral tubule junctions, and, as a consequence, reticulophagy is blocked and misfolded proteins accumulate in the ER. Overexpression of the ER tubulating domain of DNM1L/DRP1, a multifunctional PINK1 kinase substrate that localizes to ER-mitochondria contact sites, increases junctions and restores reticulophagy. Our findings show that PINK1 shapes the ER to target misfolded proteins for RTN3L-SEC24C-mediated macroreticulophagy at defined ER sites, peripheral tubule junctions.

Keywords: ER junctions; ER quality control; Reticulophagy

DOI: https://doi.org/10.1080/15548627.2025.2508934

Microb Cell. 2025 ;12 119-130

An adenine model of inborn metabolism errors alters TDP-43 aggregation and reduces its toxicity in yeast revealing insights into protein misfolding diseases.

Sangeun Park, Sei-Kyoung Park, Peter Blair, Susan W Liebman.

TDP-43 is linked to human diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Expression of TDP-43 in yeast is known to be toxic, cause cells to elongate, form liquid-like aggregates, and inhibit autophagy and TOROID formation. Here, we used the apt1∆ aah1∆ yeast model of inborn errors of metabolism, previously shown to lead to intracellular adenine accumulation and adenine amyloid-like fiber formation, to explore interactions with TDP-43. Results show that the double deletion shifts the TDP-43 aggregates from liquid-like droplets toward a more amyloid-like state. At the same time the deletions reduce TDP-43's effects on toxicity, cell morphology, autophagy, and TOROID formation without affecting the level of TDP-43. This suggests that the liquid-like droplets rather than amyloid-like TDP-43 aggregates are responsible for the deleterious effects in yeast. How the apt1∆ aah1∆ deletions alter TDP-43 aggregate formation is not clear. Possibly, it results from adenine and TDP-43 fiber interactions as seen for other heterologous fibers. This work offers new insights into the potential interactions between metabolite-based amyloids and pathological protein aggregates, with broad implications for understanding protein misfolding diseases.

Keywords: ALS; FRAP; TDP-43; liquid-like droplets; metabolism disorders; metabolite-based amyloids; yeast

DOI: https://doi.org/10.15698/mic2025.05.850

Trends Endocrinol Metab. 2025 May 26. pii: S1043-2760(25)00081-5. [Epub ahead of print]

Understanding metabolic resilience by unraveling temporal dynamics of cellular responses.

Paniz Jasbi, Alex E Mohr, Meghana Hosahalli Shivananda Murthy, Judith Klein-Seetharaman.

Metabolic resilience is essential for organismal homeostasis under diverse external pressures, because responding and adapting to stressors requires energy and drives changes at every omic level. The goal of this paper is to synthesize recent advances in understanding the intricate interplay, especially between metabolic and transcriptomic responses, involved in addressing external perturbations. We highlight the importance of timing and sequence in immediate and long-term adjustments; furthermore, we underscore the evolutionary significance of metabolic resilience and its potential for developing innovative therapeutic interventions, making it a timely contribution to contemporary biological, biomedical, and environmental research fields.

Keywords: evolutionary biology; microbiota; multiomics; robustness; stress adaptation; stress resistance

DOI: https://doi.org/10.1016/j.tem.2025.04.006