PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming

Breast cancer is a predominant cause of cancer‑related mortality among women, particularly aggressive subtypes such as triple‑negative breast cancer (TNBC), which currently lack effective targeted therapies. While PTEN‑induced kinase 1 (PINK1) is known for its role in maintaining mitochondrial homeostasis via mitophagy, its specific contributions to breast cancer progression and metabolic regulation remain poorly defined. The present study aimed to investigate the oncogenic potential of PINK1 and its influence on metabolic reprogramming. To achieve this, the PINK1 expression levels in breast cancer tissues and cell lines were assessed. Gain‑ and loss‑of‑function methodologies were employed in luminal (MCF‑7) and TNBC (MDA‑MB‑231) cells. Then, mitophagy was evaluated by measuring LC3‑II levels, Parkin expression and utilizing transmission electron microscopy. Glucose uptake assays and metabolite quantification (including pyruvate and acetyl‑CoA) were conducted. Reverse transcription‑quantitative polymerase chain reaction identified phosphoglycerate kinase 2 (PGK2) as a downstream target of PINK1. Functional assays were then performed to examine the proliferation, migration and invasion of cells with PINK1 overexpression. The results demonstrated that PINK1 overexpression increased mitophagy and induced a glycolytic phenotype, characterized by enhanced glucose uptake and elevated PGK2 levels. Elevated concentrations of pyruvate and acetyl‑CoA indicated increased metabolic flux. Functionally, PINK1 promoted proliferation, migration and invasion in both cell types. Knockdown of PGK2 reversed these effects, underscoring its critical role in PINK1‑mediated metabolic reprogramming. Transcriptomic data obtained from online databases revealed a correlation between high PINK1 expression and immunosuppressive tumor microenvironments, as well as poor prognosis. The PINK1‑PGK2 axis constitutes a critical mechanism linking mitophagy to glycolytic reprogramming in breast cancer, representing a novel therapeutic target, particularly for TNBC. Targeting this axis may yield new strategies for addressing treatment‑resistant, metabolically adaptive breast cancer.