Biology subjects

Tamargo-Gomez, I.

Publications and source records attributed to Tamargo-Gomez, I..

3 recordsLinked to original sources

bioRxiv2025

ATG4D loss leads to late-onset cardiomyopathy and stress-induced heart failure in mice, and its repression marks maladaptive cardiac remodeling in humans

In the last years, autophagy has emerged as an essential pathway for most cellular functions. Basal autophagy plays a protective role as a quality control mechanism by which damaged or noxious cellular components are degraded and cellular organelles are periodically renewed. Moreover, autophagic activity can be increased in situations of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, or the presence of intracellular pathogens. Normally, induction of autophagy is protective, although in some circumstances, such as conditions of hemodynamic stress, autophagosome accumulation upon autophagy induction can be a maladaptive process. The deficiency of the autophagic protease ATG4D in mice leads to the accumulation of cellular autophagosomes in most tissues, including the heart. Here, we show that the increased autophagosome content of atg4d-/- mice is linked to the development of late-onset cardiomyopathy and to increased susceptibility to heart failure induced by transverse aortic constriction. Furthermore, we report the existence of human ATG4D variants associated with cardiovascular pathologies and also that ATG4D expression is reduced in human obstructive hypertrophic cardiomyopathy and dilated cardiomyopathy, which highlights a conserved cardio-protective role of the ATG4D protease.

pathology↗

bioRxiv2025

Reduced systemic autophagy by simultaneous loss of ATG4B, ATG4C and ATG4D leads to accelerated aging in mice

Autophagy is an essential catabolic pathway that safeguards cellular and tissue homeostasis, yet the systemic consequences of its impairment in mammals remain poorly defined because complete autophagy ablation is embryonic or perinatal lethal. Here, we generate ATG4A-only mice, a model in which ATG4A is the sole remaining ATG4 protease due to combined ATG4B/C/D deletion. Through comprehensive biochemical and cellular analyses, we delineate the in vivo substrate specificity of ATG4A and demonstrate that it sustains only minimal ATG8 priming, uncovering a previously unrecognized functional asymmetry within the mammalian ATG4-ATG8 system. ATG4A-only mice exhibit a profound but incomplete whole-body autophagy deficiency that disrupts multiple organ systems and triggers a premature aging syndrome marked by increased DNA damage, systemic senescence, metabolic dysfunction, and dramatically shortened lifespan. Integrating these findings with comparisons to additional ATG4-deficient models, we show that organismal longevity scales with residual autophagic competence. Together, our work reveals how graded reductions in autophagy integrity influence tissue fitness and aging, establishing autophagic capacity as a key determinant of mammalian lifespan.

cell biology↗

bioRxiv2022

Autophagy alterations in white and brown adipose tissues of mice exercised under different training protocols

Autophagy is a conserved catabolic process that promotes cellular homeostasis and health. Although exercise is a well-established inducer of this pathway, little is known about the effects of different types of training protocols on the autophagy levels of tissues that are tightly linked to the obesity pandemic (like brown adipose tissue) but not easily accessible in humans. Here, we take advantage of animal models to assess the effects of short- and long-term resistance and endurance training in both white and brown adipose tissue, reporting distinct alterations on autophagy proteins LC3B and p62. For instance, both short-term endurance and resistance training protocols increased the levels of these proteins in white adipose tissue before this similarity diverges during long training, while autophagy regulation appears to be far more complex in brown adipose tissue. Additionally, we also analyzed the repercussion of these interventions in fat tissues of mice lacking autophagy protease ATG4B, further assessing the impact of exercise in these dynamic, regulatory organs (which are specialized in energy storage) when autophagy is limited. In this regard, only resistance training could slightly increase the presence of lipidated LC3B, while p62 levels increased in white adipose tissue after short-term training but decreased in brown adipose tissue after long-term training. Altogether, our study suggests an intricated regulation of exercise-induced autophagy in adipose tissues that is dependent on the training protocol and the autophagy competence of the organism.

molecular biology↗