FEBS Letters

doi: 10.1002/1873-3468.14925pmid: N/A

Yu, Young Suk; Kim, Ik Soo; Baek, Sung Hee

doi: 10.1002/1873-3468.70060pmid: 40346781

Autophagy is a conserved catabolic process that is essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy exhibits a context‐dependent dual role: In early stages, autophagy acts as a tumor suppressor by preserving genomic integrity and limiting oxidative stress. In advanced stages, autophagy supports tumor progression by facilitating metabolic adaptation, therapy resistance, immune evasion, and metastasis. This review highlights the molecular mechanisms underlying this dual function and focuses on the transcriptional and epigenetic regulation of autophagy in cancer cells. Key transcription factors, including the MiT/TFE family, FOXO family, and p53, as well as additional regulators, are discussed in the context of stress‐responsive pathways mediated by mTORC1 and AMPK. A deeper understanding of the transcriptional and epigenetic regulation of autophagy in cancer is crucial for developing context‐specific therapeutic strategies to either promote or inhibit autophagy depending on the cancer stage, thereby improving clinical outcomes in cancer treatment.

Attanasio, Sergio

doi: 10.1002/1873-3468.70061pmid: 40342093

Autophagy is a catabolic process by which cells maintain cellular homeostasis through the degradation of dysfunctional cytoplasmic components, such as toxic misfolded proteins and damaged organelles, within the lysosome. It is a multistep process that is tightly regulated by nutrient, energy, and stress‐sensing mechanisms. Autophagy plays a pivotal role in various biological processes, including protein and organelle quality control, defense against pathogen infections, cell metabolism, and immune surveillance. As a result, autophagy dysfunction is linked to a variety of pathological conditions. The role of autophagy in cancer is complex and dynamic. Depending on the context, autophagy can have both tumor‐suppressive and pro‐tumorigenic effects. In contrast, its role is more clearly defined in protein conformational disorders, where autophagy serves as a mechanism to reduce toxic protein aggregation, thereby improving cellular homeostasis. Because autophagy‐based therapies hold promising potential for the treatment of cancer and protein conformational disorders, this review will highlight the latest findings and advancements in these areas.

Gunes, Damla; Ustal, Alara; Ertem, Yusuf Emre; Akkoc, Yunus; Gozuacik, Devrim

doi: 10.1002/1873-3468.70139pmid: 40804788

Relapse and metastasis continue to be major factors in cancer patient morbidity and death. Cancer dormancy is one of the reasons why cancer recurs after months or years of treatment. With the ability to reactivate, dormant tumors are transitioning into a growth latency stage that shields them from immune surveillance and traditional chemotherapy medications. Over the past decade, research efforts have concentrated on understanding processes governing the dormant state better. The ultimate goal of these efforts is to improve cancer diagnosis, treatment of metastatic illness, and prevention of relapse. Cancer tolerance to stress may depend on autophagy, a cellular stress and recycling system that promotes cancer growth and survival. Recent studies indicated that autophagy may help cancer cells to survive in primary and metastatic environments, to withstand treatment, to develop a dormant state, and to transition from the dormancy to a proliferative state. In this Review, we will discuss the autophagy–dormancy connection in primary and metastatic cancer.

Mühlenhoff, Ulrich; Trauth, Dominik; Śliwińska, Weronika; Boss, Linda; Lill, Roland

doi: 10.1002/1873-3468.70129pmid: 40768618

Mitochondria contain the bacteria‐inherited iron–sulfur cluster assembly (ISC) machinery to generate cellular iron–sulfur (Fe/S) proteins. Mutations in human ISC genes cause severe disorders with a broad clinical spectrum and are associated with strong defects in mitochondrial Fe/S proteins, including respiratory complexes I–III. For unknown reasons, complex IV (aka cytochrome c oxidase), a non‐Fe/S, heme‐containing enzyme, is severely affected. Using yeast as a model, we show that depletion of Rsm22, the counterpart of the human mitoribosome assembly factor METTL17, phenocopies the defects observed upon impairing late‐acting ISC proteins, that is, diminished activities of mitoribosomal translation and respiratory complexes III and IV. Rsm22 binds Fe/S clusters in vivo, thereby satisfactorily explaining the defect of respiratory complex IV in ISC‐deficient cells, because this complex contains three mitochondrial DNA‐encoded subunits.

Dieter, Emily M.; Larson, James; Tokmina‐Lukaszewska, Monika; Xiong, Jin; Green, Jared; Guo, Yisong; Broderick, William E.; Bothner, Brian; Broderick, Joan B.

doi: 10.1002/1873-3468.70120pmid: 40715996

Methanogenic archaea are particularly rich in iron–sulfur proteins, yet their roles remain largely enigmatic. Here, we characterized a Methanococcus voltae (Mvo) protein from the domain of unknown function (DUF) 2193 family, a group of proteins present primarily in archaea and characterized by a conserved cysteine‐rich C‐terminal motif. MvoDUF2193 was heterologously expressed and characterized by a range of spectroscopic and analytical methods. The results demonstrate that MvoDUF2193 binds a single [4Fe–4S] cluster per subunit and that cluster occupancy regulates the transition from an apo tetramer to a [4Fe–4S] monomeric form. We hypothesize that MvoDUF2193 serves a regulatory role in the cell, mediated by [Fe–S] cluster binding and changes in oligomeric state.

Jordt, Laura Magdalena; Gellert, Manuela; Zelms, Finja; Bekeschus, Sander; Lillig, Christopher Horst

doi: 10.1002/1873-3468.70072pmid: 40400140

Glutaredoxin 3 (Grx3) is a multidomain protein (Trx‐GrxA‐GrxB) with a Trx‐like domain and two Grx domains containing a CGFS motif for binding Fe2S2 clusters. To study the function of these domains, HeLa cells with GLRX3 knockout were generated via CRISPR/Cas. The knockout activated iron‐regulatory protein 1, indicating iron starvation due to impaired iron metabolism. Transfection with constructs encoding wild‐type or individual domains showed that only the Trx‐GrxA construct could rescue the phenotype, matching the effect of full‐length Grx3. The specific role of the second Grx domain in human Grx3, absent in simpler eukaryotes such as yeast, remains unclear. While the individual domains are insufficient to rescue the knockout of full‐length Grx3, the Trx‐GrxA module is functionally critical.

Dasgupta, Pratik; Kanaujia, Shankar Prasad

doi: 10.1002/1873-3468.70068pmid: 40387417

Di Napoli, Giulia; Fissore, Alex; Salladini, Edoardo; Raccuia, Eleonora; Oliaro‐Bosso, Simonetta; Ruggiero, Alessia; Berisio, Rita; Medina, Milagros; Velazquez‐Campoy, Adrian; Adinolfi, Salvatore; Marengo, Mauro

doi: 10.1002/1873-3468.70117pmid: 40667721

Tuberculosis remains a critical global health challenge, which underscores the need for new therapeutic targets. A potential drug target is the rhodanese‐like thiosulfate sulfurtransferase SseA, which plays a role in macrophage infection by Mycobacterium tuberculosis (Mtb) and its resistance to oxidative stress. In our research, we identified a protein (Rv3284), herein referred to as SufEMtb, that interacts with SseA and modulates its activity. Sequence analysis and molecular modeling revealed that SufEMtb enhances SseA enzymatic function by binding to its non‐catalytic N‐terminal domain and favoring an activating conformational change in a regulatory loop of SseA. This interaction appears crucial for effective enzyme activity and the maintenance of redox homeostasis in Mtb, making the SseA–SufEMtb complex a potential target for new therapies.

Takahashi, Yutaro S.; Kohga, Hidetaka; Chek, Min Fey; Yamamoto, Kotomi; Takahashi, Jun F.; Shigematsu, Hideki; Tanaka, Yoshiki; Ichikawa, Muneyoshi; Miyazaki, Ryoji; Hakoshima, Toshio; Tsukazaki, Tomoya

doi: 10.1002/1873-3468.70135