bims-tofagi 2026-06-07 papers

Issue of 2026–06–07
four papers selected by
Michele Frison, University of Cambridge

Front Cell Dev Biol. 2026 ;14 1817489

Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy.

Xiaowen Huang, Zichang Guo, Bowen Liu, Hongyun Tang.

Targeting dihydroorotate dehydrogenase (DHODH) to restrict de novo pyrimidine synthesis is a promising anticancer strategy. However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies. Here, using mt-Keima-based mitophagy reporters and CRISPR/Cas9-mediated gene knockout models, we reveal a critical adaptive mechanism whereby BQR-induced mitochondrial reactive oxygen species (mtROS) trigger protective mitophagy. Crucially, we demonstrate that inhibiting this autophagy process synergistically enhances BQR's anti-tumor activity both in vitro and in vivo. This combination leads to enhanced mtROS accumulation and severe lipid peroxidation, ultimately triggering caspase-dependent apoptosis, while ferroptosis does not appear to be the dominant mechanism under these conditions. Our findings identify mitophagy as a key mechanism of resistance to DHODH inhibition and provide a strong rationale for a combinatorial strategy to enhance the therapeutic efficacy of this class of drugs.

Keywords: ATG7; DHODH inhibition; apoptosis; chloroquine; mitophagy; mtROS

DOI: https://doi.org/10.3389/fcell.2026.1817489

J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):

A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.

Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.

Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.

DOI: https://doi.org/10.1083/jcb.202511088

Trends Mol Med. 2026 Jun 04. pii: S1471-4914(26)00115-2. [Epub ahead of print]

Deubiquitinases at organelle quality control bottlenecks in neurodegeneration.

Lisa M Ellerby, Avraham Ashkenazi.

Neurodegenerative diseases with prominent motor symptoms converge on mitochondrial and lysosomal bottlenecks in selectively vulnerable neurons. Deubiquitinases regulate ubiquitin-dependent organelle fate at these decision points. Emerging evidence suggests that modulating deubiquitinase activity can restore organelle quality control and represents a promising therapeutic strategy.

Keywords: Parkinson’s disease; polyglutamine expansion diseases; proteostasis; ubiquitin enzymes

DOI: https://doi.org/10.1016/j.molmed.2026.05.006

Redox Biol. 2026 May 30. pii: S2213-2317(26)00240-5. [Epub ahead of print]95 104242

CHK1 activates mitophagy to attenuate cardiac aging via inhibiting AHSA1-ubiquitination.

Peng Jing, Liu-Hua Zhou, Shu-Xuan Chen, Jia-Yi Chen, Ling-Feng Gu, Tong-Tong Yang, Si-Bo Wang, Chong Du, Yi-Xi Chen, Qi-Ming Wang, Lian-Sheng Wang, Hao Wang.

With the acceleration of global population aging, the progressive deterioration of cardiac structure and function has become a critical determinant of cardiovascular health, presenting a significant public health challenge. Checkpoint kinase 1 (CHK1), a key cell cycle checkpoint protein, plays an essential role in various biological processes by mediating signaling cascades. While CHK1 has been shown to be important for heart regeneration, its role in the aging process of the heart remains unclear. In this study, we investigated the alterations in CHK1 expression in aging hearts and elucidated the underlying regulatory mechanisms. In both in vivo and in vitro models, CHK1 expression was significantly downregulated during aging. To assess its functional role, we generated cardiomyocyte-specific CHK1 overexpression and knockout mice and compared their cardiac performance. We found that CHK1 overexpression alleviated age-associated cardiac dysfunction, while CHK1 knockout worsened cardiac function in aged mice. Furthermore, CHK1 overexpression significantly attenuated doxorubicin (DOX)-induced acutely senescence in adult mouse cardiomyocytes (AMCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic studies revealed that CHK1 overexpression delayed cardiac aging by activating heat shock protein 90 (HSP90)-mediated mitophagy. Immunoprecipitation and mass spectrometry (IP-MS) analyses demonstrated that CHK1 directly interacts with the activator of HSP90 ATPase homolog 1 (AHSA1), thereby suppressing TRIM8-mediated ubiquitination and degradation, facilitating AHSA1-HSP90 complex formation, and enhancing HSP90 ATPase activity. Overall, our results suggest that CHK1 overexpression activates mitophagy via the AHSA1-HSP90 pathway to mitigate cardiac aging. This study highlights the critical role of CHK1 in cardiac aging and proposes a potential therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Keywords: AHSA1; CHK1; Cardiac aging; HSP90; Mitophagy

DOI: https://doi.org/10.1016/j.redox.2026.104242