iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification

Verma, Manish; Francis, Lily; Lizama, Britney N.; Callio, Jason; Fricklas, Gabriella; Wang, Kent Z.Q.; Kaufman, Brett A.; D’Aiuto, Leonardo; Stolz, Donna B.; Watkins, Simon C.; Nimgaonkar, Vishwajit L.; Soto-Gutiérrez, Alejandro; Goldstein, Amy; Chu, Charleen T.

doi:10.1016/j.ajpath.2022.11.002

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…With respect to chemoresistant disease, despite intrinsic OxPhos limitations, mitochondrial membrane potential (ΔΨ m ) is either sustain or hyperpolarized in drug resistant AML cells 3,24 . Because mitochondrial hyperpolarization typically tracks with high OxPhos, the low OxPhos yet hyperpolarized phenotype of drug resistant AML cells is unexpected and as such, highly diagnostic of cell-intrinsic mitochondrial remodeling 25,26 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Hagen,

Montgomery,

Aruleba

et al. 2024

Preprint

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Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, primarily stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of our hypothesis, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well the endogenous F1-ATPase inhibitor ATP5IF1. In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

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Section: Introductionmentioning

confidence: 99%

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Hagen,

Montgomery,

Aruleba

et al. 2024

Preprint

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show abstract

“…To date, there has been a few reported uses of the iPSCs model for the study of Alpers' syndrome resulting from POLG mutation, and focused only on iPSCs and derived 2D neurons 26 , 27 . In this study, we established an iPSCs model of Alpers' syndrome, generated from the skin fibroblasts of one Alpers' patient.…”

Section: Introductionmentioning

confidence: 99%

The NAD⁺ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease

Hong,

Zhang,

Yangzom

et al. 2024

Int. J. Biol. Sci.

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

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Inflammation and aging: signaling pathways and intervention therapies

Zhang

et al. 2023

Sig Transduct Target Ther

190

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

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iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification

Cited by 3 publications

References 45 publications

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

The NAD⁺ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease

Inflammation and aging: signaling pathways and intervention therapies

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iPSC-Derived Neurons from Patients with POLG Mutations Exhibit Decreased Mitochondrial Content and Dendrite Simplification

Cited by 3 publications

References 45 publications

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease

Inflammation and aging: signaling pathways and intervention therapies

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The NAD⁺ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease