Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells DOI Creative Commons

Meri Walter‐Manucharyan,

Melanie Martin,

Julia Pfützner

и другие.

Development Growth & Differentiation, Год журнала: 2024, Номер 66(8), С. 398 - 413

Опубликована: Окт. 1, 2024

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in process stem cell differentiation, including differentiation neural cells (NSCs). Here we studied importance mtDNA function early NSCs two culture models: CGR8-NS line was derived from embryonic by lineage selection technique, primary were isolated day 14 mouse fetal forebrain. We detected dramatic increase content upon NSC to adapt levels differentiated state, which not accompanied changes mitochondrial transcription factor A expression. As chemical depletion ethidium bromide failed generate living ρ° lines both types, used inhibition polymerase-γ 2'-3'-dideoxycytidine reduce replication subsequently cellular content. Inhibition reduced neurogenesis but gliogenesis. The did change energy production/consumption or reactive oxygen species (ROS) model used. In conclusion, is essential for gliogenesis through as yet unknown mechanisms, which, however, largely independent energy/ROS metabolism.

Язык: Английский

Inflammation and aging: signaling pathways and intervention therapies DOI Creative Commons
Xia Li, Chentao Li, Wanying Zhang

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 8, 2023

Abstract Aging is characterized by systemic chronic inflammation, which accompanied cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there an urgent need for a systematic organization inflammaging through dimensionality reduction. Factors secreted senescent cells, known as senescence-associated secretory phenotype (SASP), promote inflammation can induce senescence in normal cells. At same time, accelerates immune resulting weakened function inability to clear cells inflammatory factors, creates vicious cycle senescence. Persistently elevated levels organs such bone marrow, liver, lungs cannot be eliminated leading damage aging-related Therefore, has been recognized endogenous factor elimination could potential strategy anti-aging. Here we discuss at molecular, cellular, organ, disease levels, review current aging models, implications cutting-edge single cell technologies, well anti-aging strategies. Since preventing alleviating diseases improving overall quality life are ultimate goals research, our highlights critical features mechanisms along with latest developments future directions providing theoretical foundation novel practical

Язык: Английский

Процитировано

547
What can ATP content tell us about Barth syndrome muscle phenotypes? DOI Open Access
Jeffrey J. Brault, Simon J. Conway

Journal of Translational Genetics and Genomics, Год журнала: 2025, Номер 9(1), С. 1 - 10

Опубликована: Янв. 15, 2025

Adenosine triphosphate (ATP) is the energy currency within all living cells and involved in many vital biochemical reactions, including cell viability, metabolic status, death, intracellular signaling, DNA RNA synthesis, purinergic synaptic active transport, muscle contraction. Consequently, altered ATP production frequently viewed as a contributor to both disease pathogenesis subsequent progression of organ failure. Barth syndrome (BTHS) an X-linked mitochondrial characterized by fatigue, skeletal weakness, cardiomyopathy, neutropenia, growth delay due inherited TAFAZZIN enzyme mutations. BTHS widely hypothesized literature be model defective leading deficits. Prior patient data have linked impaired reduced phosphocreatine ratios (PCr/ATP) children adult hearts muscles, suggesting primary role for perturbed energetics. Moreover, although only limited direct measurements content ADP/ATP ratio (an indicator available from hydrolysis) so far been carried out, analysis divergent animal models, cultured types, diverse organs has failed uncover unifying understanding molecular mechanisms linking deficiency This review mainly focuses on energetics striated mitochondriopathy.

Язык: Английский

Процитировано

2
The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease DOI Creative Commons
Yu Hong, Zhuoyuan Zhang, Tsering Yangzom

и другие.

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(4), С. 1194 - 1217

Опубликована: Янв. 1, 2024

Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding catalytic subunit of polymerase-gamma (POLG), which essential for mitochondrial DNA (mtDNA) replication.The disease progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus.The neurological features are intractable epilepsy developmental regression, with no effective treatment; underlying mechanisms still elusive, partially due lack good experimental models.Here, we generated patient derived induced pluripotent stem cells (iPSCs) one carrying compound heterozygous mutations A467T (c.1399G>A) P589L (c.1766C>T), further differentiated them into cortical organoids neural (NSCs) mechanistic studies dysfunction syndrome.Patient exhibited a phenotype that faithfully replicated molecular changes found postmortem brain tissue, as evidenced neuronal loss depletion mtDNA complex I (CI).Patient NSCs showed leading ROS overproduction downregulation NADH pathway.More importantly, NAD + precursor nicotinamide riboside (NR) significantly ameliorated defects organoids.Our findings demonstrate iPSC model vitro models disease; this first-in-its-kind cell platform enables therapeutic exploration has identified NR viable drug candidate and, potentially, other diseases similar causes.

Язык: Английский

Процитировано

3
Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy DOI
James T. Hagen, McLane M. Montgomery, Raphael Taiwo Aruleba

и другие.

Science Advances, Год журнала: 2025, Номер 11(15)

Опубликована: Апрель 9, 2025

OxPhos inhibitors have struggled to show a clinical benefit because of their inability distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique acute myeloid leukemia (AML) Unlike cells that couple respiration ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix consumption allows survive stress. Thus, hypothesized may resist chemotherapy-induced cell death reversing the synthase reaction. In support, BCL-2 inhibition with venetoclax abolished flux without affecting mitochondrial polarization. surviving cells, sustained depended on matrix consumption. Mitochondrial was further enhanced in made refractory venetoclax, consequential down-regulations endogenous F 1 -ATPase inhibitor ATP5IF1. Knockdown ATP5IF1 conferred resistance, while overexpression impaired activity and heightened sensitivity venetoclax. These data identify as cancer cell–intrinsic vulnerability context targeted chemotherapy.

Язык: Английский

Процитировано

0
Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy DOI Creative Commons
James T. Hagen, McLane M. Montgomery, Raphael Taiwo Aruleba

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 15, 2024

ABSTRACT Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique mitochondria inside acute myeloid leukemia (AML) cells. Unlike cells which couple respiration the synthesis of ATP, AML were discovered support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows survive stress, hypothesized that may resist cell death induced OxPhos damaging chemotherapy reversing synthase reaction. In this, targeted inhibition BCL-2 with venetoclax abolished flux without impacting mitochondrial potential. surviving cells, sustained was dependent on consumption. Mitochondrial further enhanced in made refractory venetoclax, consequential downregulations both proton-pumping respiratory complexes, as well endogenous F 1 -ATPase inhibitor ATP5IF1 . treatment-naive AML, knockdown sufficient drive resistance, while overexpression impaired activity and heightened sensitivity venetoclax. Collectively, our data identify a cancer-cell intrinsic vulnerability context chemotherapy.

Язык: Английский

Процитировано

1
Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells DOI Creative Commons

Meri Walter‐Manucharyan,

Melanie Martin,

Julia Pfützner

и другие.

Development Growth & Differentiation, Год журнала: 2024, Номер 66(8), С. 398 - 413

Опубликована: Окт. 1, 2024

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in process stem cell differentiation, including differentiation neural cells (NSCs). Here we studied importance mtDNA function early NSCs two culture models: CGR8-NS line was derived from embryonic by lineage selection technique, primary were isolated day 14 mouse fetal forebrain. We detected dramatic increase content upon NSC to adapt levels differentiated state, which not accompanied changes mitochondrial transcription factor A expression. As chemical depletion ethidium bromide failed generate living ρ° lines both types, used inhibition polymerase-γ 2'-3'-dideoxycytidine reduce replication subsequently cellular content. Inhibition reduced neurogenesis but gliogenesis. The did change energy production/consumption or reactive oxygen species (ROS) model used. In conclusion, is essential for gliogenesis through as yet unknown mechanisms, which, however, largely independent energy/ROS metabolism.

Язык: Английский

Процитировано

0