bims-smemid 2026-07-19 papers

Int J Mol Sci. 2026 Jul 01. pii: 5931. [Epub ahead of print]27(13):

The Role of Apoptosis and Ferroptosis in Primary Mitochondrial Diseases: Mechanisms and Pathogenesis.

Anastasia Kolotova, Alexandr Shestopalov, Sergey Kutsev.

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases-caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation-and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes-including volume reduction and cristae loss-represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber's hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers-such as lipid peroxidation products, decreased GPX4, and iron deposition-rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition-using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers-together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis-ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.

Keywords: apoptosis; ferroptosis; iron metabolism; lipid peroxidation; mitochondria; mitochondrial diseases; molecular crosstalk; oxidative stress; regulated cell death; tissue specificity

DOI: https://doi.org/10.3390/ijms27135931

Cell Stress. 2026 ;10 49-52

Polyamine-mediated inhibition of ferroptosis contributes to geroprotection.

Frank Madeo, Didac Carmona-Gutierrez, Guido Kroemer.

Geroprotection aims at extending healthspan by delaying age-associated pathologies. Polyamines including spermine and spermidine are interconvertible metabolites whose longevity-promoting effects have traditionally been attributed to autophagy induction. In addition, recent evidence identifies spermine as an endogenous Fe2+ chelator that suppresses ferroptosis, thereby complementing the autophagy-inducing activity of spermidine. Indeed, spermidine inhibits EP300 acetyltransferase activity and supports hypusination-dependent activation of TFEB, both leading to autophagy. However, enhanced autophagic flux may increase susceptibility to ferroptosis through ferritinophagy and lipid remodeling. In parallel, polyamine catabolism generates H2O2 and acrolein, both of which facilitate lipid peroxidation and ferroptotic demise. The discovery that spermine directly chelates redox-active Fe2+ closes a conceptual gap by explaining how polyamine supplementation can promote longevity while avoiding excessive ferroptotic cell loss. Multiple lines of evidence including metabolomics, isotope tracing, cell-free lipid peroxidation systems, Fe2+-binding biophysics, mass spectrometry, Raman spectroscopy, nuclear magnetic resonance and disease models demonstrate that spermine limits labile iron and ferroptosis. Together, these findings support a unified model in which spermidine-driven autophagy and spermine-mediated ferroptosis inhibition cooperate to preserve tissue homeostasis and healthspan.

Keywords: Aging; autophagy; cell death; metabolism; spermidine; spermine

DOI: https://doi.org/10.15698/cst2026.07.318

FEBS Open Bio. 2026 Jul 15.

A yeast model of 5-oxoproline accumulation reveals a general toleration to 5-oxoproline.

Pratiksha Dubey, Vaishnavi Sanjayan, Praveen Singh, Shantanu Sengupta, Anand Kumar Bachhawat.

5-oxoproline (5-OP) or pyroglutamic acid is an intermediate in the degradation arc of the glutathione cycle. It is metabolized into glutamate through the action of the 5-oxoprolinase enzyme, the only enzyme known to act on this metabolite. 5-OP has long been known to be relatively inert with a proposed role as an osomoprotectant. Recent studies on the 5-oxoprolinase enzyme in mammalian cells have, however, shown that knockdown or deletion of 5-oxoprolinase makes mice (and humans) prone to heart failure, an effect ascribed to oxidative stress caused by a twofold increase in 5-OP. To examine the consequences of 5-oxoproline accumulation more rigorously, we created a yeast model for 5-oxoproline accumulation. Using this model, we observed retardation of growth only when intracellular levels of 5-OP were increased 12- to 20-fold over normal levels. Performing an analysis of transcriptomic changes under these conditions, we observed a large number of genes were differentially regulated and while there was no unifying dysregulated pathway, there was an upregulation of various efflux pumps. Ultimately, modulating the expression of these genes by knockout or overexpression highlighted that many of the upregulated genes were involved in the cellular response to 5-OP accumulation. However, our results failed to show any significant oxidative stress response. In conclusion, our study suggests a need to reevaluate previous suppositions of the 5-OP induced oxidative stress response and proposes alternate mechanisms for this effect.

Keywords: 5‐oxoproline (5‐OP); glutathione metabolism; pyroglutamic acid; redox; transcriptomics; yeast model

DOI: https://doi.org/10.1002/2211-5463.70254