Abstract
Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A−/−) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3β, LC3II/I ratio, Atg5–Atg12 complex and Atg7 in the cortex of BVR-A−/− mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy.
Highlights
Biliverdin reductase (BVR) is an evolutionarily conserved and ubiquitously expressed enzyme involved in the heme degradation pathway
Age-associated changes to levels of protein-bound HNE and 3-NT and mammalian target of rapamycin (mTOR) expression and activation were evaluated in the cortex of Biliverdin reductase-A (BVR-A)−/− and WT mice at 2, 6 and 11 months of age, with the aim to understand whether loss of BVR-A influences these processes
We found that levels of p-mTORSer2448, the active form of the protein, are significantly and positively associated with the levels of most of the autophagy-related proteins we evaluated in the current study only in WT and not in BVR-A−/− mice (Table 2)
Summary
Biliverdin reductase (BVR) is an evolutionarily conserved and ubiquitously expressed enzyme involved in the heme degradation pathway. Two different isoforms of BVR were detected in humans and named BVR-A and BVR-B [3]. Both isozymes catalyze the reduction of biliverdin, BVR-A selectively reduces biliverdin IXα to bilirubin IXα, one of the strongest endogenous antioxidants [3,4]. BVR-A can translocate to the nucleus acting as a bZIP-type transcription factor, controlling the expression of genes involved in stress-responses [6,7,8,9,10]. BVR-A was reported to play a pivotal role in regulating
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