bims-tofagi 2026-09-27 papers

Issue of 2026–09–27
five papers selected by
Michele Frison, University of Cambridge

Aging Cell. 2026 Oct;25(10): e70720

Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis.

Ning Jin, Li Zhou, Haixia Gui, Jingjing Tang, Xiaozhen Huang, Wenting Wang, Guorong Jin, Haiqin Cheng, Yuxiang Liang, Xinyi Geng, Zhiwei Peng, Hong Zhao, Zhizhen Liu, Jun Xie.

Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.

Keywords: HIF‐3α‐BNIP3 axis; aging heart; mitochondrial transplantation; mitophagy flux

DOI: https://doi.org/10.1111/acel.70720

Free Radic Biol Med. 2026 Sep 19. pii: S0891-5849(26)01164-0. [Epub ahead of print]256 618-635

Dysfunctional mitophagy in Alzheimer's disease: evidence from peripheral optineurin.

Simone Patergnani, Alessandro Trentini, Valentina Rosta, Paola Guindani, Alessandro Greatti, Dario Pedrini, Giorgia Meneguzzo, Leonardo Rigon, Nicola Filippini, Elena Giusto, Giovanni Zuliani, Paolo Pinton, Carlo Cervellati.

Mitophagy and mitochondrial quality-control pathways are impaired in Alzheimer's disease (AD), but the relevance of peripheral mitophagy markers and their regulation during sustained amyloid-β (Aβ) stress remain unclear. We investigated whether serum optineurin, a mitophagy receptor, is altered in mild cognitive impairment (MCI) and AD, and explored mitophagy dynamics in an in vitro model of Aβ1-42-induced mitochondrial stress. To achieve this aim, serum optineurin was measured in 458 older individuals, including controls and patients with AD, mild cognitive impairment (MCI), and mixed Alzheimer's disease/vascular dementia (MIXED). Complementary in vitro experiments were performed in SH-SY5Y neuroblastoma cells exposed to Aβ1-42 over time, to evaluate mitochondrial function, oxidative stress, lipid peroxidation, lactate release, Parkin/optineurin recruitment, mitophagy, mitochondrial quality-control markers, apoptosis, and cell viability. Serum optineurin was markedly lower in MCI and AD groups than in controls (p < 0.001 for both) and was also reduced in MIXED (p < 0.001). Serum 4-HNE was increased in MCI and AD, consistent with systemic oxidative stress. In vitro, Aβ1-42 induced an early increase in mitophagy and optineurin expression, followed by a later decline associated with impaired mitochondrial quality-control markers, apoptotic activation, and reduced cell viability. In conclusion, optineurin emerges as a candidate peripheral biomarker associated with AD and MCI. In vitro, Aβ1-42 exposure was associated with an early increase in mitophagy-related responses followed by progressive mitochondrial dysfunction, oxidative stress, apoptotic activation, and reduced cell viability. These findings support the relevance of optineurin within mitochondrial quality-control pathways under AD-related stress.

Keywords: Alzheimer's disease; Dementia; Mitochondrial dysfunction; Mitophagy; Optineurin

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.09.013

Antioxidants (Basel). 2026 Aug 22. pii: 1051. [Epub ahead of print]15(9):

Mitochondrial Quality Control Impairment Is a Hallmark of TDP-43G376D ALS Patient-Derived Fibroblasts.

Giuseppe Petito, Maria Ventriglia, Victoria Stefania Del Fiore, Arianna Cuomo, Federica Cioffi, Francesco Manfrevola, Flora Guerra, Lucia Bertuccini, Giulia Ricci, Gilda Cobellis, Antonia Lanni, Cecilia Bucci, Roberta Romano, Rosalba Senese.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder strongly associated with mitochondrial dysfunction and impaired proteostasis. Mutations in TARDBP, encoding TAR DNA-binding protein 43 (TDP-43), contribute to disease pathogenesis through cytoplasmic mislocalization and aggregation. Among these, the ALS-linked TDP-43G376D mutation has been previously associated with oxidative stress, mitochondrial fragmentation, and impaired oxidative phosphorylation. Here, we investigated the impact of TDP-43G376D on Mitochondrial Quality Control (MQC) pathways using patient-derived dermal fibroblasts carrying the mutation at early and advanced disease stages, complemented by HEK293T and Neuro2a cellular models expressing mutant TDP-43. We show that TDP-43G376D impairs mitophagic flux, as evidenced by reduced delivery of damaged mitochondria to lysosomes. This was accompanied by pronounced disruption of mitochondrial cristae architecture and accumulation of mitochondrial DNA damage, indicating compromised mitochondrial genome integrity. Furthermore, TDP-43G376D induces sustained activation of the mitochondrial Unfolded Protein Response (UPRmt), consistent with persistent mitochondrial stress, while selectively impairing the sirtuin-dependent antioxidant branch. In parallel, activation of the Endoplasmic Reticulum UPR (UPRER) was observed, indicating a coordinated engagement of cellular stress pathways. Collectively, our findings identify coordinated alterations in multiple MQC pathways associated with TDP-43G376D rather than isolated mitochondrial defects, supporting further investigation of these pathways in larger and disease-relevant ALS models.

Keywords: Amyotrophic Lateral Sclerosis (ALS); Endoplasmic Reticulum stress; Mitochondrial Quality Control (MQC); TDP-43; mitochondrial Unfolded Protein Response (UPRmt); mitochondrial dysfunction; mitophagy; oxidative stress

DOI: https://doi.org/10.3390/antiox15091051

Nat Commun. 2026 Aug 25. pii: 10135. [Epub ahead of print]17(1):

Protein entanglement misfolding influences whether proteins undergo proteasomal degradation or persist in near-native misfolded states.

Yang Jiang, Anushka Jain, Sina Ghaemmaghami, Edward P O'Brien.

A novel class of protein misfolding involving changes in entanglement status occurs across the bacterial cytosolic proteome and likely exists in many other organisms. Here, we test whether this class of misfolding has measurable consequences for protein homeostasis by examining its relationship with ubiquitin-mediated proteasomal degradation immediately after protein synthesis. Integrating protein structural information with ubiquitin mass spectrometry (Ubq-MS) data from human fibroblasts, we find that proteins containing native non-covalent lasso entanglements (NCLEs), which are known to be more prone to misfolding, are 93% (95% Confidence Interval: 44-160%) more likely to be ubiquitinated and targeted for proteasomal degradation than proteins lacking native entanglements. Coarse-grained folding simulations further show that ubiquitinated proteins with native entanglements are four-fold more likely to misfold than non-ubiquitinated proteins without entanglements. These results suggest that entanglement misfolding, primarily through failure to form native entanglements, increases susceptibility to proteasomal degradation. We further estimate that approximately one-third of the globular proteome populates near-native entanglement-misfolded states that evade proteasomal degradation because they remain structurally similar to the native ensemble. Given that entanglement misfolding is inherent to the polymeric nature of proteins, these findings are likely applicable across diverse organisms.

DOI: https://doi.org/10.1038/s41467-026-76875-9