Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model. DOI Open Access

R. Mendel,

Seiki Matsuno,

Alex Lu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

ABSTRACT S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control lack SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation implicated in homeostasis, screened library modulating compounds determine their comparative effects rescue unfolded protein (UPR mt ) stress induction uaDf5 worms. Interestingly, Thiamine was discovered be an effective positive control, significantly reducing model. Two lead therapeutic candidates from were Hemin Celastrol (Tripterin). is activating anti-inflammatory metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) reduced animals mitophagy-dependent fashion. This study highlights utility worm model enable preclinical identification candidate leads SLSMD-based identifies possible serve as modulators improve health specifically reduce heteroplasmy levels diseases.

Language: Английский

Mitophagy at the oocyte-to-zygote transition promotes species immortality DOI Open Access
Siddharthan Balachandar Thendral,

Sasha Bacot,

Katherine S. Morton

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. oocyte is the source all zygotic 2 mitochondrial under strict developmental regulation early oogenesis 3–5 . Yet, fully developed oocytes exhibit presence deleterious DNA (mtDNA) 6,7 dysfunction from high levels endogenous reactive oxygen species 8 exogenous toxicants 9 How prevent transmission damaged to zygotes unknown. Here we discover that onset oocyte-to-zygote transition (OZT) developmentally triggers a robust rapid mitophagy event term at OZT (MOZT). We show MOZT requires fragmentation, activation macroautophagy system receptor FUNDC1, but not prevalent factors PINK1 BNIP3. Oocytes upregulate expression FUNDC1 in response diverse insults, including mtDNA mutations damage, uncoupling stress, dysfunction, thereby promoting selection against mitochondria. Loss leads increased inheritance impaired bioenergetic progeny, resulting diminished extinction descendent populations. Our findings reveal FUNDC1-mediated as mechanism preserves mother-to-offspring promotes continuity. These results may explain how mature many harboring mutant give rise healthy embryos with reduced mtDNA.

Language: Английский

Citations

0
Caenorhabditis elegans RAC1/ced-10 mutants as a new animal model to study very early stages of Parkinson’s disease DOI Creative Commons
Amanda Muñoz‐Juan, Núria Benseny‐Cases, Saurav Guha

et al.

Progress in Neurobiology, Journal Year: 2024, Volume and Issue: 234, P. 102572 - 102572

Published: Jan. 21, 2024

Patients with Parkinson's disease (PD) display non-motor symptoms arising prior to the appearance of motor signs and before a clear diagnosis. Motor correlate progressive deposition protein alpha-synuclein (Asyn) both within outside central nervous system, its accumulation parallels neurodegeneration. The genome Caenorhabditis elegans does not encode homolog Asyn, thus rendering this nematode an invaluable system which investigate PD-related mechanisms in absence interference from endogenous Asyn aggregation. CED-10 is human RAC1, small GTPase needed maintain function survival dopaminergic neurons against Asyn-induced toxicity C. elegans. Here, we introduce RAC1/ced-10 mutants as predictive tool early PD neurodegeneration occurs. Deep phenotyping these animals reveals that, development, they displayed altered defecation cycles, GABAergic abnormalities increased oxidation index. Moreover, exhibited lipid metabolism evidenced by droplets. Lipidomic fingerprinting indicates that phosphatidylcholine sphingomyelin, but phosphatidylethanolamine or phosphatidylserine, were elevated mutant nematodes. These collective characteristics reflect dysfunction, neurotransmission defects, upregulation stress response mechanisms, metabolic changes associated early-onset PD. Thus, put forward easy-to-manipulate preclinical animal model deepen our understanding early-stage accelerate translational path for therapeutic target discovery.

Language: Английский

Citations

3
Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes DOI

Ritoprova Sen,

Cuckoo Teresa Jetto,

Ravi Manjithaya

et al.

Journal of Biosciences, Journal Year: 2024, Volume and Issue: 49(1)

Published: Feb. 19, 2024

Language: Английский

Citations

3
Caenorhabditis elegans as a Model to Study Aging and Photoaging DOI Creative Commons

Saowanee Jeayeng,

Jirapan Thongsroy, Sirithip Chuaijit

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(10), P. 1235 - 1235

Published: Sept. 30, 2024

(

Citations

1
Identification and experimental validation of programmed cell death- and mitochondria-associated biomarkers in osteoporosis and immune microenvironment DOI Creative Commons
Xiu Yang,

Zhengchao Zhang,

Yun-Nan Lu

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: July 26, 2024

Prior research has demonstrated that programmed cell death (PCD) and mitochondria assume pivotal roles in controlling cellular metabolism maintaining bone equilibrium. Nonetheless, the comprehensive elucidation of their mode operation osteoporosis (OP) warrants further investigation. Therefore, this study aimed at analyzing role genes associated with PCD (PCD-RGs) (mortality factor-related genes; MRGs) OP.

Language: Английский

Citations

0
Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in the C. elegans uaDf5 animal model. DOI Open Access

R. Mendel,

Seiki Matsuno,

Alex Lu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

ABSTRACT S ingle large s cale m itochondrial DNA (mtDNA) d eletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control lack SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation implicated in homeostasis, screened library modulating compounds determine their comparative effects rescue unfolded protein (UPR mt ) stress induction uaDf5 worms. Interestingly, Thiamine was discovered be an effective positive control, significantly reducing model. Two lead therapeutic candidates from were Hemin Celastrol (Tripterin). is activating anti-inflammatory metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) reduced animals mitophagy-dependent fashion. This study highlights utility worm model enable preclinical identification candidate leads SLSMD-based identifies possible serve as modulators improve health specifically reduce heteroplasmy levels diseases.

Language: Английский

Citations

0