Biology subjects

Dogan, S. A.

Publications and source records attributed to Dogan, S. A..

3 recordsLinked to original sources

bioRxiv2026

ULK1-linked mitophagy promotes cardiac hypoxia tolerance in the blind mole-rat

Blind mole-rats (BMRs) thrive in chronically hypoxic subterranean environments, displaying exceptional cardiac resilience to conditions that rapidly induce failure in other mammals. Here, we integrate in vivo physiology, multi-omics profiling, mitochondrial analyses, and genome editing to uncover an evolved cardioprotective program in BMRs. Under acute 0% O2 exposure, BMRs exhibit markedly prolonged survival compared to mouse. At the molecular level, BMR hearts undergo coordinated metabolic remodeling, restrained inflammatory signaling, and enhanced genome maintenance. Functionally, BMR cardiac mitochondria suppress high-flux oxidative phosphorylation and reverse electron transport-associated ROS following hypoxia, indicating intrinsic adaptation to oxygen collapse. Hypoxia selectively activates AMPK-mTOR-ULK1 dependent mitophagy, and pharmacological manipulation demonstrates that mitophagy is required for BMR cardiomyocyte survival during hypoxia-reoxygenation stress. Finally, we identify a BMR-specific insertion in ULK1 and demonstrate that introduction of this sequence into rat cardiomyocytes enhances hypoxia tolerance in a mitophagy-dependent manner. These findings reveal an evolutionarily tuned mitochondrial quality-control strategy that enables extreme cardiac resilience to hypoxia.

cell biology↗

bioRxiv2024

ALS driven by mutant NEK1 aggregation is accelerated by Pml loss, but clinically reversed through pharmacologic induction of Pml-mediated degradation

Germinal mono-allelic loss-of-function mutations of NEK1 drive Amyotrophic Lateral Sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1t) is aggregation-prone, particularly in alpha-motoneurons (MNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1t/t). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1wt/t animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1t proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1t aggregates in MNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of NEK1 aggregates in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that not only promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, but also facilitates the clearance of protein aggregates, yielding dramatic clinical improvement. These observations validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein aggregation.

pathology↗

bioRxiv2023

Tumor-induced alterations in single-nucleus transcriptome of atrophying muscles indicate enhanced protein degradation and reduced oxidative metabolism

Tumor-induced skeletal muscle wasting in the context of cancer cachexia is a condition with profound implications for patient survival. The loss of muscle mass is a significant clinical obstacle and is linked to reduced tolerance to chemotherapy and increased frailty. We investigated muscle gene expression at single nucleus level in cachectic mice and revealed distinct myonuclear gene signatures and a shift towards type IIb myonuclei. Notably, atrophy-related genes, including Atrogin1, MuRF1 and Eda2r were upregulated in these myonuclei, emphasizing their crucial role in muscle wasting. Activation of the Ectodysplasin A2 Receptor (EDA2R) pathway suppressed gene sets related to muscle contraction and oxidative metabolism, indicating its involvement in transcriptional reprogramming. Our study also highlighted the negative impact of tumors on oxidative metabolism in muscle tissue and their influence on the transcriptomes of mononuclear cells in skeletal muscle. These findings contribute to a deeper understanding of the molecular mechanisms underlying cancer cachexia.

cell biology↗