bims-tofagi 2025-10-05 papers

Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2502841122

Mitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway.

The homeostatic link between the production of mitochondrial ROS (mtROS) and mitophagy plays a significant role in how cells respond to various physiological and pathological conditions. However, it remains unclear how cells translate oxidative stress signals into adaptive mitophagy responses. Here, we show that mtROS act as signaling molecules that activate the ataxia-telangiectasia mutated (ATM)-cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway. When activated, CHK2 regulates three critical steps in mitophagy. First, CHK2 phosphorylates mitochondrial membrane protein ATAD3A at Ser371, which inhibits the transport of PINK1 to the inner mitochondrial membrane and leads to the accumulation of PINK1 and the commencement of mitophagy. Second, activated CHK2 targets the autophagy adaptor OPTN at Ser177 and Ser473, thereby enhancing the targeting of ubiquitinated mitochondria to autophagosomes. Finally, CHK2 phosphorylates Beclin 1 at Ser90 and Ser93, hence promoting the formation of autophagosomal membranes. Consistent with these effects, Chk2-/- mice show impaired mitophagic induction and impaired recovery in a ROS-dependent model of renal ischemia-reperfusion. Our study reveals a mtROS-triggered adaptive pathway that coordinates mitophagic induction, in order to protect cells and tissues exposed to pathophysiological stress-induced damage.

Keywords: ATM; CHK2; PINK1; mitophagy; mtROS

DOI: https://doi.org/10.1073/pnas.2502841122

Sci Adv. 2025 Oct 03. 11(40): eadw7376

The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

DOI: https://doi.org/10.1126/sciadv.adw7376

Cell Biochem Funct. 2025 Oct;43(10): e70125

A Review of FUN14 Domain-Containing 1 Involvement in Mitochondrial Biological Processes and Mechanisms Across Various Systems.

Hailun He, Xin Zhang, Lidan Xiong, Xiao Qin.

FUN14 domain-containing 1 (FUNDC1), an outer mitochondrial membrane protein, has emerged as a critical regulator of mitochondrial quality control and cellular homeostasis. Initially identified as a mitophagy receptor, FUNDC1 orchestrates hypoxia-induced mitophagy through phosphorylation-dependent interactions with LC3. Recent studies reveal its multifaceted roles in mitochondrial dynamics (fission/fusion), mitochondria-associated endoplasmic reticulum membranes (MAMs), and metabolic regulation, mediated by posttranslational modifications (phosphorylation, ubiquitination, acetylation). FUNDC1 dysfunction is implicated in cardiovascular diseases, neurodegeneration, cancer, and dermatological pathologies. It modulates oxidative stress primarily through impaired clearance of ROS-generating mitochondria via disrupted mitophagy, while also influencing apoptosis, pyroptosis, and inflammation via crosstalk with Bcl-2 family proteins, MOMP, mPTP, and cGAS-STING pathways. This review synthesizes FUNDC1's molecular mechanisms, highlighting its dual role as a protector (clearing damaged mitochondria) and potentiator of injury (excessive mitophagy). We also discuss therapeutic targeting of FUNDC1-dependent pathways in mitochondrial disorders.

Keywords: FUNDC1; MAMs; metabolic diseases; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.1002/cbf.70125

Brain Res. 2025 Sep 27. pii: S0006-8993(25)00533-5. [Epub ahead of print]1867 149970

BNIP3L/NIX-mediated mitophagy: Future directions in Alzheimer's disease.

Violina Kakoty, Khang Wen Goh, Prashant Kesharwani, Young Tag Ko.

BCL2-interacting protein 3 like (BNIP3L) /Nip3-like protein X (NIX) is a mitochondrial outer membrane protein possessing mitophagic and pro-apoptotic properties. Mitochondrial dysfunction and subsequent mitophagy impairment are some of the early triggers for Alzheimer's Disease (AD), which is a progressive neurodegenerative condition affecting memory, thinking, and behavior. AD is associated with mitochondrial protein impairment and mitophagy failure. A recent study showed downregulation in BNIP3L expression in response to stress hormone release during Alzheimer's, and pretreatment with a BNIP3L enhancer of a corticosterone-exposed mouse upregulated mitophagy. This research proved that BNIP3L stimulation can be an effective therapeutic strategy against Alzheimer's. However, BNIP3L-mediated mitophagy studies focused on Alzheimer's have been relatively scarce, and expanding knowledge on its regulatory proteins will help lay a smoother road ahead for future Alzheimer's research. In this review, we aim to summarize all the recent findings of the downstream proteins of BNIP3L, which play an indispensable role in inducing BNIP3L-mediated mitophagy effects. The review also explicates the significance of healthy mitochondria and normally functioning mitophagy in Alzheimer's. Finally, the review states the implications of BNIP3L in other diseases, like cardiovascular conditions and cancer, underscoring the immense potential of this wonder protein.

Keywords: Alzheimer’s Disease; BCL2-interacting protein 3-like/Nip3-like protein X; Downstream proteins; Mitophagy

DOI: https://doi.org/10.1016/j.brainres.2025.149970