A Novel Non‐Apoptotic Role of Procaspase‐3 in the Regulation of Mitochondrial Biogenesis Activators

Abstract

The executioner caspase-3 has been proposed as a pharmacological intervention target to preserve degenerating dopaminergic (DA) neurons because apoptotic mechanisms involving caspase-3 contribute, at least in part, to the loss of DA neurons in patients and experimental models of Parkinson's disease (PD). Here, we determined that genetic intervention of caspase-3 was sufficient to prevent cell death against oxidative stress (OS), accompanied by unexpected severe mitochondrial dysfunction. Specifically, as we expected, caspase-3-deficient DA neuronal cells were very significantly resistant to OS-induced cell death, while the activation of the initiator caspase-9 by OS was preserved. Moreover, detailed phenotypic characterization of caspase-3-deficient DA cells revealed severe mitochondrial dysfunction, including an accumulation of damaged mitochondria with a characteristic swollen structure and broken cristae, reduced membrane potential, increased levels of reactive oxygen species (ROS), and deficits in mitochondrial oxidative phosphorylation (OXPHOS) enzymes. Of great interest, we found that mitochondrial biogenesis was dramatically decreased in caspase-3-deficient DA cells, whereas their capability of mitophagy was normal. In accordance with this observation, caspase-3 gene knock down (KD) resulted in dramatically decreased expression of the key transcriptional activators of mitochondrial biogenesis, such as Tfam and Nrf-1, implicating a non-apoptotic role of procaspase-3 in mitochondrial biogenesis. Therefore, a prolonged anti-apoptotic intervention targeting caspase-3 should be considered with caution due to the potential adverse effects in mitochondria dynamics resulting from a novel potential functional role of procaspase-3 in mitochondrial biogenesis via regulating the expression of mitochondrial biogenesis activators. J. Cell. Biochem. 119: 347-357, 2018. © 2017 Wiley Periodicals, Inc.

Spermidine rescues the deregulated autophagic response to oxidative stress of osteoarthritic chondrocytes

“…This possibly indicates that also in chondrocytes SPD is effective in counteracting CP3 activity as previously reported in nervous cells [52], thus preventing endonuclease activation [37]. At the same time SPD may sustain a mitochondrial activity of caspase 3, recently put in connection with mitochondrial biogenesis [53].…”

Is Mitochondria Biogenesis and Neuronal Loss Prevention in Rat Hippocampus Promoted by Apigenin?

“…Some pro-apoptotic signals are potent inducers of mitochondrial biogenesis. At the dose used by the authors, 50 mg/ kg by oral gavage every day, the flavone apigenin can induce the early expression of procaspase-3, which is crucial for the activation of mitochondrial biogenesis initiators, such as TFAM and NRF-1 (Kim, Ha, Yang, & Son, 2018). In this perspective, a significant role is ruled by the PGC-1α, the expression of which is particularly stringent for mitochondrial biogenesis (Chen, Tao, Li, & Yao, 2018;Niu, Tang, Ren, & Feng, 2018).…”

Genome-wide DNA methylation patterns in Autism Spectrum Disorder and mitochondrial function

“…For example, CUL3 plays a role in polyubiquitination and the degradation of proteins, with rare mutations of this gene seen in individuals with ASD (58,59). Degradation of damaged mitochondria also occurs via caspase–dependent cell death (20), with caspase-3 proposed as a target to prevent the progression of Parkinson’s Disease (60). Caspases are a family of protease enzymes playing essential roles in programmed cell death and Caspase-2 is differentially methylated in our dataset (Table S5) and is involved in stress-induced cell death pathways and is implicated in neurodegenerative disorders like Alzheimer’s Disease, Huntington’s disease and temporal lobe epilepsy (61).…”