Interest in tumor cell mitochondria as a pharmacological target has been rekindled in recent years. This attention is due in part to new publications documenting heterogenous characteristics of solid tumors, including anoxic and hypoxic zones that foster cellular populations with differentiating metabolic characteristics. These populations include tumor-initiating or cancer stem cells, which have a strong capacity to adapt to reduced oxygen availability, switching rapidly between glycolysis and oxidative phosphorylation as sources of energy and metabolites. Additionally, this cell subpopulation shows high chemo- and radioresistance and a high capacity for tumor repopulation. Interestingly, it has been shown that inhibiting mitochondrial function in tumor cells affects glycolysis pathways, cell bioenergy, and cell viability. Therefore, mitochondrial inhibition may be a viable strategy for eradicating cancer stem cells. In this context, medicinal chemistry research over the last decade has synthesized and characterized “vehicles” capable of transporting novel or existing pharmacophores to mitochondrial tumor cells, based on mechanisms that exploit the physicochemical properties of the vehicles and the inherent properties of the mitochondria. The pharmacophores, some of which have been isolated from plants and others, which were synthesized in the lab, are diverse in chemical nature. Some of these molecules are active, while others are prodrugs that have been evaluated alone or linked to mitochondria-targeted agents. Finally, researchers have recently described drugs with well-proven safety and efficacy that may exert a mitochondria-specific inhibitory effect in tumor cells through noncanonical mechanisms. The effectiveness of these molecules may be improved by linking them to mitochondrial carrier molecules. These promising pharmacological agents should be evaluated alone and in combination with classic chemotherapeutic drugs in clinical studies.

Cardiomyopathy is commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD), even when they have normal renal function and arterial pressure. The role of cardiomyocyte polycystin-1 (PC1) in cardiovascular pathophysiology remains unknown. PC1 is a potential regulator of BIN1 that maintains T-tubule structure, and alterations in BIN1 expression induce cardiac pathologies. We used a cardiomyocyte-specific PC1-silenced (PC1-KO) mouse model to explore the relevance of cardiomyocyte PC1 in the development of heart failure (HF), considering reduced BIN1 expression induced T-tubule remodeling as a potential mechanism. PC1-KO mice exhibited an impairment of cardiac function, as measured by echocardiography, but no signs of HF until 7–9 months of age. Of the PC1-KO mice, 43% died suddenly at 7 months of age, and 100% died after 9 months with dilated cardiomyopathy. Total BIN1 mRNA, protein levels, and its localization in plasma membrane-enriched fractions decreased in PC1-KO mice. Moreover, the BIN1 + 13 isoform decreased while the BIN1 + 13 + 17 isoform was overexpressed in mice without signs of HF. However, BIN1 + 13 + 17 overexpression was not observed in mice with HF. T-tubule remodeling and BIN1 score measured in plasma samples were associated with decreased PC1-BIN1 expression and HF development. Our results show that decreased PC1 expression in cardiomyocytes induces dilated cardiomyopathy associated with diminished BIN1 expression and T-tubule remodeling. In conclusion, positive modulation of BIN1 expression by PC1 suggests a novel pathway that may be relevant to understanding the pathophysiological mechanisms leading to cardiomyopathy in ADPKD patients.

Introduction: Lung cancer remains the leading cause of cancer-related mortality worldwide. Drug resistance is a major limitation of current therapies, prompting the search for new treatment strategies. Lung tumors frequently develop a hypoxic microenvironment associated with aggressive behavior and unfavorable clinical outcomes. Tumor-initiating cells (TICs), also known as cancer stem cells, and hypoxia-driven metabolic adaptations contribute significantly to therapy resistance. Mitochondrial destabilization has emerged as a promising invariant target in TICs. Triphenylphosphonium (TPP ⁺ )-conjugated hydroxybenzoates selectively accumulate in the mitochondrial matrix, driven by membrane potential, disrupting organelle function. Additionally, doxycycline inhibits mitochondrial biogenesis and reduces mitochondrial mass. Here, we evaluate a therapeutic strategy combining TPP ⁺ -conjugated lipophilic cations with doxycycline to target mitochondrial vulnerability in non-small cell lung cancer. Methods: TPP ⁺ lipophilic cations conjugated to benzoate derivatives, alone or combined with doxycycline, were evaluated for their ability to disrupt mitochondrial function, reduce cell viability, and induce apoptosis in two lung cancer cell lines under normoxic and hypoxic conditions. Results: Our results demonstrate that these compounds exhibit cytotoxicity in lung cancer cells, particularly under hypoxic conditions, consistent with mitochondrial functional impairment. Combinations of TPP ⁺ C ₁₀ /doxycycline and GA-TPP ⁺ C ₁₀ /doxycycline exhibited synergistic cytotoxicity in both normoxia and hypoxia, and increased apoptotic cell death compared to monotherapies. Conclusion: Targeting mitochondrial functions using mitochondria-directed compounds, particularly in combination with doxycycline, represents a promising therapeutic approach for lung cancer. This strategy may be especially effective in hypoxic microenvironments, where conventional therapies often fail. Further in vivo validation is warranted to support the translational potential of this approach.