Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Yang, Liu; Guttman, Lauren; Dawson, Valina L.; Dawson, Ted M.

doi:10.1016/j.bcp.2024.116174

Cited by 3 publications

(1 citation statement)

References 214 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Parthanatos, however, is independent of caspase activation and dependent on PARP activation; thus, it can be rescued with PARP inhibitors. Parthanatos has been mostly studied in the context of neurodegenerative diseases and stroke, in which it was first described ( 42 , 46 ). However, recent findings indicate that cancer cells are also susceptible to parthanatos ( 47 , 48 ), which represents a therapeutic opportunity to kill cancer cells that are resistant to other types of death.…”

Section: Introductionmentioning

confidence: 99%

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

Geroyska,

Mejia,

Chan

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases. Myristoylation is emerging as a promising cancer therapeutic target, however the molecular determinants of sensitivity to N-myristoyltransferase inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that N-myristoyltransferases are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.

show abstract

Section: Introductionmentioning

confidence: 99%

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

Geroyska,

Mejia,

Chan

et al. 2024

Cancer Research Communications

View full text Add to dashboard Cite

show abstract

An introduction to the special issue “Sam Enna legacy of excellence”

Piette,

LeCount

2024

Biochemical Pharmacology

View full text Add to dashboard Cite

Interplay of mitochondrial calcium signalling and reactive oxygen species production in the brain

Angelova,

Abramov

2024

Biochemical Society Transactions

View full text Add to dashboard Cite

Intracellular communication and regulation in brain cells is controlled by the ubiquitous Ca2+ and by redox signalling. Both of these independent signalling systems regulate most of the processes in cells including the cell surviving mechanism or cell death. In physiology Ca2+ can regulate and trigger reactive oxygen species (ROS) production by various enzymes and in mitochondria but ROS could also transmit redox signal to calcium levels via modification of calcium channels or phospholipase activity. Changes in calcium or redox signalling could lead to severe pathology resulting in excitotoxicity or oxidative stress. Interaction of the calcium and ROS is essential to trigger opening of mitochondrial permeability transition pore — the initial step of apoptosis, Ca2+ and ROS-induced oxidative stress involved in necrosis and ferroptosis. Here we review the role of redox signalling and Ca2+ in cytosol and mitochondria in the physiology of brain cells — neurons and astrocytes and how this integration can lead to pathology, including ischaemia injury and neurodegeneration.

show abstract

Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Cited by 3 publications

References 214 publications

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

N-Myristoytransferase Inhibition Causes Mitochondrial Iron Overload and Parthanatos in TIM17A-Dependent Aggressive Lung Carcinoma

An introduction to the special issue “Sam Enna legacy of excellence”

Interplay of mitochondrial calcium signalling and reactive oxygen species production in the brain

Contact Info

Product

Resources

About