Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells

Abstract

Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.

Genome‐wide screening identifies novel genes and biological processes implicated in cisplatin resistance

“…ARIH1 has been shown recently to be widely overexpressed in cancer cells, notably in breast and lung adenocarcinomas, and to protect against cisplatin-induced cell death by promoting clearance of damaged mitochondria (mitophagy) (45). ARIH1 has also been shown to protect against cisplatin-induced apoptosis by ubiquitinating EIF4E2, irrespective of the status of p53 or caspase-3 (22).…”

PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function

“…Neurotransmitter uptake was significantly impaired in PINK1 KO hDANs ( Figure 5F and Figure 5G) and this could not be rescued by inhibition of uptake in the vesicles (VMAT), DA synthesis via TH or DA degradation (COMT/MAO) ( Figure 5H). We measured the amount of oxidized catecholamines and did not observe any 14 differences between PINK1 KO hDANs and their control with or without L-DOPA treatment ( Figure 5H). Therefore, DA loss cannot be explained by oxidation but conversion to neuromelanin is still possible but difficult to detect in iPSC-derived 2D…”

“…We found PINK1 KO hDANs contain more disperse, larger particles compared to their healthy control ( Figure 4A). Next we fractionated hDAN lysates by density and used marker proteins to identify the soluble fractions (8)(9)(10)(11)(12)(13)(14) and the cholesterol-rich floating fractions (3-7) marked by flotillin ( Figure 4B). We assessed the distribution of several membrane-bound and cytosolic Since the dopamine transporter DAT is known to be negatively regulated by its phosphorylation in cholesterol rich lipid membrane rafts 74 reviewed in 75 , we then assessed the distribution of phosphorylated DAT and total DAT.…”

“…PINK1 PD has an early occurrence of L-DOPA-associated dyskinesia, slow disease progression and absence of cognitive impairment 3,4 and affective and psychotic symptoms are frequently part of the clinical presentation 5 . 3 To unravel the molecular function of PINK1, Knockouts (KOs) of the PINK1 gene in mice, drosophila, zebrafish and cancer cells have been generated indicating that PINK1 deficiency causes mitochondrial dysfunction, altered mitochondrial morphology, disturbed mitochondrial quality control and iron and calcium toxicity [6][7][8][9][10][11][12][13][14][15] .…”

“…The pathogenic action of PINK1 mutations could be cell type specific. PINK1 is highly expressed in the brain but it is also expressed throughout the rest of the body and has been associated with disease mechanisms in several tissues 41,42 including the progression of some cancers 14,43 . PINK1 is reportedly expressed predominantly in neurons 44 but has been found highly expressed in myelinating oligodendrocytes in the human cortex 45 .…”