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

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.