Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by increased activation of fibroblasts/myofibroblasts. Previous reports have shown that IPF fibroblasts are resistant to apoptosis, but the mechanisms remain unclear. Since inhibition of the mitochondrial permeability transition pore (mPTP) has been implicated in the resistance to apoptosis, in this study, we analyzed the role of mitochondrial function and the mPTP on the apoptosis resistance of IPF fibroblasts under basal conditions and after mitomycin C-induced apoptosis. We measured the release of cytochrome c, mPTP opening, mitochondrial calcium release, oxygen consumption, mitochondrial membrane potential, ADP/ATP ratio, ATP concentration, and mitochondrial morphology. We found that IPF fibroblasts were resistant to mitomycin C-induced apoptosis and that calcium, a well-established activator of mPTP, is decreased as well as the release of pro-apoptotic proteins such as cytochrome c. Likewise, IPF fibroblasts showed decreased mitochondrial function, while mPTP was less sensitive to ionomycin-induced opening. Although IPF fibroblasts did not present changes in the mitochondrial membrane potential, we found a fragmented mitochondrial network with scarce, thinned, and disordered mitochondria with reduced ATP levels. Our findings demonstrate that IPF fibroblasts are resistant to mitomycin C-induced apoptosis and that altered mPTP opening contributes to this resistance. In addition, IPF fibroblasts show mitochondrial dysfunction evidenced by a decrease in respiratory parameters.

Hypoxia and hypoxia-inducible factors (HIFs) are essential in regulating several cellular processes, such as survival, differentiation, and the cell cycle; this adaptation is orchestrated in a complex way. In this review, we focused on the impact of hypoxia in the physiopathology of idiopathic pulmonary fibrosis (IPF) related to lung development, regeneration, and repair. There is robust evidence that the responses of HIF-1α and -2α differ; HIF-1α participates mainly in the acute phase of the response to hypoxia, and HIF-2α in the chronic phase. The analysis of their structure and of different studies showed a high specificity according to the tissue and the process involved. We propose that hypoxia-inducible transcription factor 2a (HIF-2α) is part of the persistent aberrant regeneration associated with developing IPF.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control′s response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal interstitial lung disease characterized by excessive deposition of extracellular matrix and progressive destruction of the lung architecture. Repeated epithelial injury and aberrant tissue repair are strongly associated with its pathogenesis; however, the molecular mechanisms underlying disease progression remain incompletely understood. Altered microRNA (miRNA) expression has been extensively associated with IPF, but comparatively little attention has been given to the mechanisms regulating miRNA maturation and processing during pulmonary fibrosis. Objective: In this narrative review, we aimed to describe the relationship between IPF pathogenesis and alterations in miRNA maturation, with particular emphasis on post-transcriptional mechanisms that may disrupt the production and function of mature miRNAs. Methods: We conducted a narrative review of the available literature using PubMed, Scopus, and Google Scholar. No specific time frame was established because of the limited number of studies directly addressing miRNA maturation in IPF. Original research articles were prioritized, while relevant studies describing miRNA maturation mechanisms in other biological and disease contexts were also considered to provide mechanistic insight. Results: The available evidence suggests that alterations in miRNA maturation may contribute to miRNA dysregulation in IPF beyond changes in transcriptional control. Disruption of the Drosha/DGCR8 microprocessor complex, altered Dicer-dependent processing, and post-transcriptional modifications of miRNA precursors may affect the production of mature miRNAs. In addition, adenosine-to-inosine editing mediated by adenosine deaminases acting on RNA (ADARs) may modify miRNA sequences and influence their maturation, stability, and target selection. Mechanotransduction-associated pathways, including Hippo/YAP signaling, may further interfere with the miRNA-processing machinery. These alterations may contribute to the persistent dysregu-lation of antifibrotic miRNAs, including miR-29, thereby promoting extracellular matrix accumulation and sustaining profibrotic signaling. Conclusions: Although evidence directly linking defects in miRNA maturation to IPF remains limited, available findings support the hypothesis that alterations in post-transcriptional miRNA processing represent an additional regulatory layer contributing to pulmonary fibrosis. Further experimental studies are needed to determine how specific alterations in miRNA maturation and editing contribute to IPF pathogenesis and whether components of the miRNA-processing machinery may represent potential therapeutic targets.

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Lung adenocarcinoma (LUAD) exhibits metabolic flexibility that transcends the classical interpretation of the Warburg effect. This review proposes the concept of “adaptive mitochondrial specialization (AMS)”, an integrative framework in which mitochondria undergo coordinated, context-dependent remodeling of bioenergetic metabolism, redox homeostasis, architecture and dynamics, proteostasis, mitochondrial genome maintenance and translation, and inter-organelle communication in response to hypoxia and other tumor-associated stressors. We examine how hypoxia can promote this adaptive state through HIF-dependent metabolic reprogramming together with intrinsic mitochondrial stress responses, including respiratory-chain remodeling, proteostatic regulation, and context-dependent control of reactive oxygen species (ROS). We further discuss mitochondrial genome and translational maintenance, fusion/fission dynamics, apoptotic susceptibility, and mitochondria-associated membrane (MAM) signaling as mechanisms through which mitochondrial function can be adjusted to environmental and therapeutic stress. Beyond tumor cells, we examine how mitochondrial quality-control alterations accompany systemic metabolic remodeling during cancer cachexia and how impaired mitophagy and intercellular mitochondrial transfer can influence antitumor T-cell function. These tumor–host manifestations are considered consequences or interacting mechanisms of cancer-associated mitochondrial remodeling rather than defining criteria of AMS. Finally, we discuss how context-dependent mitochondrial and redox dependencies may expose therapeutic vulnerabilities and provide a rationale for bioenergetic stratification in precision oncology.