bims-tofagi 2024-09-29 papers

Exp Gerontol. 2024 Sep 24. pii: S0531-5565(24)00235-3. [Epub ahead of print]197 112589

Urolithin A prevents age-related hearing loss in C57BL/6J mice likely by inducing mitophagy.

Mitochondrial dysfunction with aging is associated with the development of age-related hearing loss. Mitophagy is a cardinal mechanism to maintain a healthy mitochondrial population through the turnover of damaged mitochondria. Declining mitophagy with age causes a buildup of damaged mitochondria, leading to sensory organ dysfunction. The effect of Urolithin A (UA), a mitophagy inducer, was investigated on age-related hearing loss in a mouse model. C57BL/6J mice were treated with UA from 6 to 10 months of age. UA attenuated an auditory brainstem responses (ABR) threshold shift at 8, 16, and 32 kHz frequencies, and improved mitochondrial DNA integrity and ATP production in the cochlea and auditory cortex. The mRNA levels of mitophagy-related genes and protein levels of PINK1, Parkin, BNIP3, and LC3B increased in the cochlea and auditory cortex. The expression of mitophagosomes and mitophagolysosomes in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus increased, together with the expression of Parkin and BNIP3 in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus. These results indicate that UA counteracted mitophagy decline in the auditory system and prevented age-related hearing loss. UA can be used as a potential agent to prevent age-related hearing loss.

Keywords: Age-related hearing loss; Mitochondria; Mitophagy; Urolithin A

DOI: https://doi.org/10.1016/j.exger.2024.112589

Cells. 2024 Sep 13. pii: 1540. [Epub ahead of print]13(18):

Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.

Bernardo A Bustillos, Liam T Cocker, Mathew A Coban, Caleb A Weber, Jenny M Bredenberg, Paige K Boneski, Joanna Siuda, Jaroslaw Slawek, Andreas Puschmann, Derek P Narendra, Neill R Graff-Radford, Zbigniew K Wszolek, Dennis W Dickson, Owen A Ross, Thomas R Caulfield, Wolfdieter Springer, Fabienne C Fiesel.

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Keywords: PINK1; PRKN; Parkinson disease; mitophagy; parkin; ubiquitin

DOI: https://doi.org/10.3390/cells13181540

J Cell Physiol. 2024 Sep 22. e31448

N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy.

Pingping Qi, Wei Zhang, Yang Gao, Shengkui Chen, Minghe Jiang, Rong He, Wenzhong Chen, Xiawei Wei, Bingquan Hu, Hao Xu, Minsheng Wu, Rong Tang.

N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.

Keywords: BNIP3; FTO; N6‐methyladenosine; mitophagy; sepsis

DOI: https://doi.org/10.1002/jcp.31448

Free Radic Biol Med. 2024 Sep 24. pii: S0891-5849(24)00686-5. [Epub ahead of print]

Ablation of Mitophagy Receptor FUNDC1 Accentuates Septic Cardiomyopathy through ACSL4-Dependent Regulation of Ferroptosis and Mitochondrial Integrity.

Feng-Juan Li, Huantao Hu, Liangyan Wu, Bijun Luo, Yuan Zhou, Jun Ren, Jie Lin, Russel J Reiter, Shuyi Wang, Maolong Dong, Jun Guo, Hu Peng.

Sepsis evokes compromised myocardial function prompting heart failure albeit target therapy remains dismal. Our study examined the possible role of mitophagy receptor FUNDC1 in septic cardiomyopathy. A sepsis model was established using cecal ligation and puncture (CLP) in FUNDC1 knockout (FUNDC1-/-) and WT mice prior to the evaluation of cardiac morphology, echocardiographic and cardiomyocyte contractile, oxidative stress, apoptosis, necroptosis, and ferroptosis. RNAseq analysis depicted discrepant patterns in mitophagy, oxidative stress and ferroptosis between CLP-challenged and control murine hearts. Septic patients displayed cardiac injury alongside low plasma FUNDC1 and iron levels. CLP evoked interstitial fibrosis, cardiac dysfunction (lowered ejection fraction, fractional shortening, shortening/relengthening velocity, peak shortening and electrically-stimulated intracellular Ca2+ rise, alongside increased LV end systolic diameter and relengthening duration), O2- buildup, apoptosis, necroptosis, and ferroptosis (downregulated GPX4 and SLC7A11), the responses of which were accentuated by FUNDC1 ablation. In particular, levels of lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) were upregulated following CLP procedure, with a more pronounced response in FUNDC1-/- mice. Co-immunoprecipitation and interaction interface revealed an evident interaction between FUNDC1 and ACSL4. In vitro studies revealed that the endotoxin lipopolysaccharide provoked cardiomyocyte contractile and lipid peroxidation anomalies, the responses were reversed by the mitophagy inducer oleanolic acid, inhibition of ACSL4 and ferroptosis. These findings favor a role for FUNDC1-ACSL4-ferroptosis cascade in septic cardiomyopathy.

Keywords: ACSL4; Cecal ligation and puncture; FUNDC1; Ferroptosis; Heart

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.09.039

Autoimmun Rev. 2024 Sep 19. pii: S1568-9972(24)00135-6. [Epub ahead of print]23(11): 103644

Inclusion body myositis: Correcting impaired mitochondrial and lysosomal autophagy as a potential therapeutic strategy.

Stefen Brady, Joanna Poulton, Sylviane Muller.

Inclusion body myositis (IBM) is a late onset sporadic myopathy with a characteristic clinical presentation, but as yet unknown aetiology or effective treatment. Typical clinical features are early predominant asymmetric weakness of finger flexor and knee extensor muscles. Muscle biopsy shows endomysial inflammatory infiltrate, mitochondrial changes, and protein aggregation. Proteostasis (protein turnover) appears to be impaired, linked to potentially dysregulated chaperone-mediated autophagy and mitophagy (a type of mitochondrial quality control). In this review, we bring together the most recent clinical and biological data describing IBM. We then address the question of diagnosing this pathology and the relevance of the current biological markers that characterize IBM. In these descriptions, we put a particular emphasis on data related to the deregulation of autophagic processes and to the mitochondrial-lysosomal crosstalk. Finally, after a short description of current treatments, an overview is provided pointing towards novel therapeutic targets and emerging regulatory molecules that are being explored for treating IBM. Special attention is paid to autophagy inhibitors that may offer innovative breakthrough therapies for patients with IBM.

Keywords: Autoimmunity; Autophagy; Idiopathic inflammatory myopathies; Inclusion body myositis; Mitochondrial disease; Novel treatment

DOI: https://doi.org/10.1016/j.autrev.2024.103644