PARL, short for presenilin associated rhomboid like, is a mitochondrial rhomboid protease. It belongs to the rhomboid superfamily of serine intramembrane proteases. PARL is involved in multiple crucial biological processes, especially in maintaining mitochondrial homeostasis. It processes various substrates within the cell, and is notably associated with the PINK1-PRKN/Parkin-dependent mitophagy pathway [1,2,3,4,6,8,9,10]. Mitophagy is essential for mitochondrial quality control, and PARL's role in this process is vital for normal cellular physiology [1,6].

In male mice lacking PARL, early testicular atrophy occurs due to arrested spermatogenesis during meiotic prophase I, followed by spermatocyte degeneration and death through ferroptosis. This phenotype is independent of neurodegeneration and is associated with severe mitochondrial ultrastructure abnormalities, electron transfer chain defects, disrupted coenzyme Q biosynthesis, and metabolic rewiring [5]. In Alzheimer's disease, the rs6795172 locus related to PARL is associated with clinical progression, accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures. In AD mouse models, decreased PARL expression is accompanied by elevated tau levels [7]. In ALS-FTD, CHCHD10 mutations (R15L and S59L) reduce PINK1 levels by increasing PARL activity, impairing mitophagy flux and mitochondrial Parkin recruitment [8]. In gastric cancer, NPR1 promotes cisplatin resistance by inhibiting PARL-mediated mitophagy-dependent ferroptosis [10].

In conclusion, PARL is a key protease in mitochondria, playing a crucial role in maintaining mitochondrial homeostasis, especially in processes like mitophagy. Gene knockout mouse models have revealed its significance in male infertility, Alzheimer's disease, ALS-FTD, and gastric cancer chemoresistance. These studies help in understanding the molecular mechanisms underlying these diseases and may provide potential targets for therapeutic interventions.