Genetic depletion of early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress . . . 2025, Mubaraq A Toriola

[Mij]

Full Title: Genetic depletion of early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to M1 inflammatory mode, and compromises myelin integrity in skeletal muscle, 2025, Mubaraq A Toriola et al

Abstract​

M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear. Our study shows that hemizygous deletion of early autophagy gene atg13 (Tg+/−ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, increases reactive oxygen species (ROS) in splenic macrophages, leading to its M1 polarization. Reduced macroautophagy markers WDFY3 and LC3, flow-cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), deficit of oxygen metabolism evaluated by ROS-sensor dye DCFDA, and seahorse oxygen consumption studies revealed that atg13 gene ablation impairs mitochondrial function triggering M1 polarization.

Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages contributing to the inflammatory response in M1Mφ. Additionally, the ablation of the atg13 gene resulted in the increased infiltration of M1Mφ in muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise.

These findings underscore the significance of ATG13 in post-exertional malaise (PEM).
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[Utsikt]

These are the mentions of ME/CFS in the paper. I’m not sure their descriptions are totally accurate.

The inflammatory and chronic demyelinating pathologies due to atg13 ablation could be relevant to the pathogenesis of Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS)[14] and therefore may shed light in the molecular mechanism in post-exertional malaise (PEM). PEM is a key symptom of ME/CFS[15, 16] that involves significant muscle fatigue, pain, and cognitive deficits following physical or emotional exertion. Recent literatures indicate that glucose metabolism deficits[17], reduced mitochondrial oxygen consumption [18], defective energy metabolism[19], and immune cell depletion [20] may contribute to the PEM, though the molecular mechanism remains unclear.

ME/CFS[30, 31] is a chronic inflammatory disease[32] characterized by severe muscle fatigue[33] which worsens after physical or mental exhaustion[34]. The underlying molecular mechanism is still unknown.

Consistent with our current finding, ours and other literatures also identified that the activation of NFκB, dysregulation of NO productions, and redox imbalance could play critical roles in the pathogenesis of ME/CFS. In ME/CFS, it is hypothesized that M1 macrophages, which are pro-inflammatory, could be relevant to the disease process. A study[35] suggested that classical monocytes in ME/CFS patients tend to migrate to tissues and become macrophages. High-resolution transcriptomics study after analyzing 13,000 transcriptomes in 33 ME/CFS patients followed by functional network analysis also identified upregulations of inflammatory mediators such as IL-8, NFκB, and TNF-α, associated with the M1Mφ function. Our previous study also demonstrated the activation of STAT3 in these inflammatory Mφs and downstream expressions of inflammatory cytokines such as IL6 and RANTES also play key role in the ME/CFS.

Elevated levels of inactivated phospho ATG13 have been previously reported [14] in the plasma samples of ME/CFS patients, indicating that the current findings are highly pertinent to the pathogenesis of ME/CFS. Moreover, the study of mitochondrial OXPHOS showed that ME/CFS patients have a deficiency in energy metabolism in immune cells, highlighting the relevance of our current research in the molecular mechanisms of disease progression.

They are also doing a study on rapamycin for fatigue:

Future directions: We are currently conducting a decentralized observational clinical trial of mTOR inhibitor rapamycin in the alleviation of clinical symptoms of fatigue in ME/CFS. We are collecting plasma and PBMCs from the participating subjects before and 30, 60, and 90 days after 6mg/week doses of rapamycin. In the future course of study, we will conduct a M1/M2 polarization study in PBMC-derived Mφs. Also, we will investigate once applied if plasma-borne factors could polarize human Mφs to M1 phenotype.

 

[wigglethemouse]

These are the mentions of ME/CFS in the paper. I’m not sure their descriptions are totally accurate.

Gunnar Gottschalk and Avik Roy from Simmaron are authors, hence the focus on ME/CFS. They are the ones that highlighted a difference in ATG13 in ME/CFS and running the clinical trial with rapamycin in ME/CFS.