Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Mitochondrial dysfunction is a major contributing factor to the degeneration of DA neurons [1]. Because mitochondrial dysfunction is linked with cellular damage and various age-associated diseases, the preservation of mitochondrial homeostasis is of immense importance [2]. Recent evidence indicates a potential association between mitophagy, the process responsible for clearing damaged mitochondria, and neurodegeneration in PD [3]. Nevertheless, despite this accumulating evidence, the precise role of mitophagy in the pathogenesis of PD is not known.

Nur77 is a member of the NR4A subgroup in the nuclear receptor family, which has not been associated with a natural ligand. This protein is present in the nucleus and cytoplasm of cells. Ubiquitinated Nur77 can translocate from the nucleus to the mitochondria. After reaching the mitochondria, Nur77 can interact with Parkin, thereby initiating mitophagy and recruiting Pink 1 [4]. Additionally, the mitochondria containing ubiquitinated Nur77 are more susceptible to interaction with lysosomal p62/SQSTM1, finally leading to the clearance of dysfunctional mitochondria [5]. Previous study have shown that chronic levodopa (l-Dopa) treatment can induce Nur77 transcription [6], suggesting that Nur77 may be a potential target for the treatment of PD.

c-Abl is a non-receptor tyrosine kinase of the Src family, which is an important sensor of cellular stress [7]. c-Abl is widely expressed in the brain, and it becomes activated during neurodegeneration. Studies on modification therapy for PD have mainly focused on α-synuclein (α-syn) [8]. Furthermore, studies on A53T transgenic mice have shown that upregulated expression of the active form of c-Abl increases neurodegeneration [9]. Additionally, a recent investigation showed that activated c-Abl phosphorylates parkin, thereby preventing the parkin-dependent protein clearance pathway [10,11]. Based on the central role of c-Abl activation in PD, it has been proposed that inhibiting c-Abl activation can be a potential strategy for a disease-modifying therapy [12]. Nevertheless, clinical trials with c-Abl inhibitors have not yielded a clinically significant benefit in patients with PD, potentially due to insufficient drug concentration in the brain [13]. Therefore, key factors regulating c-Abl activity should be explored.

Prohibitin 2 (PHB2) is a highly conserved mitochondrial inner membrane autophagy receptor that plays a major role in regulating mitochondrial assembly and function [[14], [15], [16]]. The LIR domain at positions 121–124 of PHB2 (YQRL) can bind to LC3 and facilitate mitophagy [17]. The Y121A/L124A mutation in the PHB2 LIR domain inhibits PHB2 binding to LC3, ultimately impairing mitophagy [18]. Our previous studies have shown that silencing PHB2 aggravates MPP+-induced mitophagy and contributes to pathological changes in PD. We have identified PHB2 as a substrate of c-Abl, and our investigations suggest that the mechanism underlying c-Abl in regulating PHB2-mediated mitophagy can be associated with the phosphorylation of PHB2 at Y121, which is evidenced by a simulated PHB2 Y121D permanent phosphorylation model [19].

In this study, we used an independently developed PHB2Y121 phosphorylated antibody to determine the role of PHB2 Y121 phosphorylation in PD mitophagy via c-Abl activation. Additionally, we elucidated the mechanism through which Nur77 suppresses the phosphorylation of PHB2 Y121 by inhibiting p-c-Abl, consequently improving mitophagy and mitigating PD pathology. Given the neuroprotective role of the Nur77-c-Abl-PHB2 pathway against DA degeneration, this study holds promise for potential therapeutic implications in PD treatment.