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Review
. 2024 Oct 24;10(21):e39684.
doi: 10.1016/j.heliyon.2024.e39684. eCollection 2024 Nov 15.

Improving understanding of ferroptosis: Molecular mechanisms, connection with cellular senescence and implications for aging

Diego De Leon-Oliva  1   2 , Diego Liviu Boaru  1   2 , Ana M Minaya-Bravo  1   2 , Patricia De Castro-Martinez  1   2 , Oscar Fraile-Martinez  1   2 , Cielo Garcia-Montero  1   2 , David Cobo-Prieto  1   3 , Silvestra Barrena-Blázquez  1   2   4 , Laura Lopez-Gonzalez  2   5 , Agustín Albillos  1   2   6 , Melchor Alvarez-Mon  1   2   7 , Miguel A Saez  1   2   8 , Raul Diaz-Pedrero  2   4   5 , Miguel A Ortega  1   2
Affiliations
Review

Improving understanding of ferroptosis: Molecular mechanisms, connection with cellular senescence and implications for aging

Diego De Leon-Oliva et al. Heliyon. .

Abstract

In the face of cell damage, cells can initiate a response ranging from survival to death, the balance being crucial for tissue homeostasis and overall health. Cell death, in both accidental and regulated forms, plays a fundamental role in maintaining tissue homeostasis. Among the regulated mechanisms of cell death, ferroptosis has garnered attention for its iron-dependent phospholipid (PL) peroxidation and its implications in aging and age-related disorders, as well as for its therapeutic relevance. In this review, we provide an overview of the mechanisms, regulation, and physiological and pathological roles of ferroptosis. We present new insights into the relationship between ferroptosis, cellular senescence and aging, emphasizing how alterations in ferroptosis pathways contribute to aging-related tissue dysfunction. In addition, we examine the therapeutic potential of ferroptosis in aging-related diseases, offering innovative insights into future interventions aimed at mitigating the effects of aging and promoting longevity.

Keywords: Aging-related diseases; Ferroptosis; Iron metabolism aging; Phospholipid (PL) peroxidation; Redox homeostasis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Mechanisms of ferroptosis execution. Peroxidation of PUFA-PLs, mainly arachidonic and adrenergic phosphatidylethanolamines (APE and AdPE, respectively), through enzyme- or radical-mediated reactions leads to increased plasma membrane tension, triggering activation of Piezo 1 and TRP channels. Altered ionic homeostasis and nanopore formation contribute to the final membrane rupture and cell lysis, probably due to NINJ1 injury. Mitochondria are characterized by reduced mitochondrial volume, increased mitochondrial membrane density, reduction or disappearance of mitochondrial cristae and rupture of the outer membrane.
Fig. 2
Fig. 2
Schematic representation of the interaction between ferroptosis, cellular senescence, oxidative stress and iron overload in aging. Ferroptosis and cellular senescence play distinct but complementary roles in the maintenance of cellular homeostasis and aging. Oxidative stress and iron overload exacerbate cellular senescence and ferroptosis, contributing to aging. The state of chronic inflammation further perpetuates cellular aging processes.
Fig. 3
Fig. 3
Role of ferroptosis in different aging-related diseases.
See this image and copyright information in PMC

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