**1. Introduction**

Cis-dichlorodiammineplatinum II (CDDP) is a platinum compound frequently used in many types of cancers [1,2]. However, the main side-effect of CDDP is its nephrotoxicity, especially in proximal tubule epithelial cells. It is estimated that 20 to 30% of patients treated with CDDP developed transient episodes of acute kidney injury, which can progress to chronic kidney disease, depending on the dose and individual pharmacokinetics [2]. The CDDP-toxicity mechanisms involve DNA damage, oxidative stress, mitochondrial damage, endoplasmic reticulum (ER) stress, autophagy, and apoptotic cell death [3,4].

In recent years, the use of biomolecules with antioxidant activity has been widely studied to mitigate the nephrotoxic effects induced by CDDP [5]. Alpha-mangostin (αM), a bioactive compound with direct antioxidant properties that can be extracted from the *Garcinia mangostana* tree, has been broadly used in

Asian traditional medicine and its nephroprotective effect has been demonstrated experimentally [6,7]. αM is a prenylated xanthone with antioxidant, anti-inflammatory, and anti-apoptotic properties [8,9]. Additionally, our research group demonstrated αM's protective effects in CDDP-induced nephrotoxicity, related to the prevention of oxidant and nitrate stress increase, glutathione decrease, tumor necrosis factor alpha (TNF-α) and p53 increase, and apoptosis induction [3,7,9]. Recently, the modulation of mitochondrial function, autophagy, and ER stress have been related to αM's protective effects in cancer and diabetic nephropathy models [10–12]. However, the participation of these processes in αM's protection in CDDP-induced nephrotoxicity has not been studied yet.

Mitochondria are double membrane organelles, which regulate important functions related to energetic homeostasis and cell death. Additionally, mitochondria are considered as one of the main reactive oxygen species (ROS) producers in the cell [13]. It is a widely accepted concept that mitochondrial damage is one of the principal mechanisms involved in CDDP-induced nephrotoxicity. CDDP induces mitochondrial membrane potential loss, as well as alterations in bioenergetics, dynamics (balance between fusion and fission), biogenesis and mitophagy, which favor the induction of apoptosis [14–17]. Additionally, the higher dependence of mitochondrial adenosine triphosphate (ATP) production in the proximal tubule compared with other nephron segments, make the proximal tubule more susceptible to CDDP-damage [2,13].

On the other hand, autophagy is a multistep pathway that degrades and recycles damaged macromolecules and organelles, to maintain intracellular homeostasis. This process involves the sequestration of damaged components inside a double membrane vesicle (autophagosome) and their subsequent degradation when the autophagosome fuses with the lysosome (autolysosome) [18]. Although autophagosome and autolysosome formation involves multiple protein complexes and multiple steps, the increase of the lipidated microtubule-associated protein 1 light chain 3 alpha (LC3) form (commonly refer as LC3-II) and the decrease of p62 levels have been widely used to evaluate the induction of autophagy [19]. In the CDDP nephrotoxicity model, it has been suggested that autophagy induction acts as a protective mechanism early on [20–22]. Recent studies also show that mitophagy (a mitochondrial-specific type of autophagy) has a protective role in CDDP nephrotoxicity [22,23]. Under mitochondrial damage or depolarization, the induction of mitophagy helps to maintain the mitochondrial quality control and, therefore, the cellular homeostasis [19]. In CDDP-induced nephrotoxicity, the mitophagy clearance of damaged mitochondria mediated by the phosphatase and tensin homologue (PTEN) induced kinase 1/parkin RBR E3 ubiquitin protein ligase (PINK1/Parkin) pathway has shown protective effects [22,24].

This study aimed to evaluate if the protective effects of αM in CCDP-induced damage in Lilly laboratory culture porcine kidney (LLC-PK1) cells, was related to αM regulation of mitochondrial function and autophagy (especially mitophagy).
