bims-tofagi 2025-02-23 papers

Issue of 2025–02–23
three papers selected by
Michele Frison, University of Cambridge

Nature. 2025 Feb 19.

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.

Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.

DOI: https://doi.org/10.1038/s41586-025-08590-2

Cell Death Differ. 2025 Feb 17.

Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC-/- Mice.

Swarna Beesetti, Cliff Guy, Shyam Sirasanagandla, Mao Yang, Rhea Jr Sumpter, Heather Sheppard, Stephane Pelletier, Marcin W Wlodarski, Douglas R Green.

Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control.

DOI: https://doi.org/10.1038/s41418-025-01461-3

Biosens Bioelectron. 2025 Feb 07. pii: S0956-5663(25)00120-4. [Epub ahead of print]276 117246

A dual-channel fluorescent probe with mitochondria-immobilization: Detecting polarity and viscosity during mitophagy.

Yue Huang, Yang Liu, Chuan Dong, Qi Zan, Feng Feng, Ruibing Wang, Shaomin Shuang.

Mitophagy is a key pathway for regulating mitochondrial quality and quantity which is essential for the preservation of cellular homeostasis. Mitophagy process may be accompanied by changes of the mitochondrial microenvironments. The multifunctional fluorescent probe is crucial for the precise detection of multiple microenvironments, which is vital for the visualization of mitophagy. Herein, a mitochondria-immobilized fluorescent probe DPP was designed and fabricated to visualize mitophagy by monitoring polarity and viscosity in dual-channel. The DPP is characterized by "D-π-A″ structure, which provides the basis for the intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) platform, enabling dual-channel responses to polarity and viscosity at emission wavelengths of 487 nm and 656 nm, respectively. The significant wavelength gap (169 nm) between the above channels prevents signal crosstalk. Additionally, the incorporation of 1, 4-dibenzyl chloride grants the probe mitochondrial immobilization capabilities, avoiding the leak of probe due to mitochondrial depolarization during autophagy. The DPP accumulates in mitochondria and monitors polarity and viscosity changes in green and red channels, respectively. Notably, the investigation of the relationship between polarity and viscosity revealed that an increase in viscosity is accompanied by a decrease in polarity. The mitophagy was effectively observed through the induction of DPP by rapamycin, with a particular emphasis on the increase in viscosity and decrease in polarity. Thus, DPP offers a powerful tool for a deeper understanding of the physiological and pathological processes associated with mitophagy and are regulated by various microenvironmental parameters.

Keywords: Fluorescent probe; Mitochondria; Polarity; Viscosity

DOI: https://doi.org/10.1016/j.bios.2025.117246