Emerging Roles of Mitochondrial Serine Protease HtrA2 in Neurodegeneration
High temperature requirement mitochondrial serine protease A2 (HtrA2), commonly known as Omi/PRSS25, is primarily known for its protein quality control function. Loss of this prime function of the protein results in neurodegenerative diseases such as Park
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Ajay R. Wagh and Kakoli Bose
Abstract
High temperature requirement mitochondrial serine protease A2 (HtrA2), commonly known as Omi/PRSS25, is primarily known for its protein quality control function. Loss of this prime function of the protein results in neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s and certain forms of epilepsy. HtrA2 belongs to the family of evolutionarily conserved proteases and is one of the core determinants of mitochondrial quality control. HtrA2 helps maintain normal mitochondrial functions during organelle biogenesis, metabolic remodelling and stress. It has been very well established that under stressful condition, HtrA2 is released from the mitochondria into the cytosol and facilitates apoptosis by binding to several members of the inhibitors of apoptosis protein (IAP) family. On the contrary, in vivo knockout studies showed a phenotype similar to Parkinson’s suggesting its involvement in neurodegeneration along with maintenance of mitochondrial homeostasis. Therefore, presence of different cellular pathways and its unique multitasking ability makes HtrA2 a potential therapeutic target. This chapter discusses different facets of HtrA2 with main focus on its role as a quality control protease and its association with neurodegenerative disorders. Keywords
Mitochondrial protein quality control • HtrA2 • Neurodegenerative disorders
A.R. Wagh • K. Bose (*) Integrated Biophysics and Structural Biology Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai 410210, Maharashtra, INDIA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 S. Chakraborti, N.S. Dhalla (eds.), Proteases in Physiology and Pathology, DOI 10.1007/978-981-10-2513-6_15
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15.1 Introduction 15.1.1 Overview of Mitochondrial Protein Quality Control Mitochondria are dynamic, semiautonomous organelles present in eukaryotic cells that play important role in energy metabolism and myriads of important physiological processes. The critical functions of mitochondria include generation of ATP through respiration, integration of several key metabolic and cofactor-generating pathways and regulation of ion homeostasis as well as apoptosis [1, 2]. Imbalance in mitochondrial homeostasis and integrity lead to severe pathophysiological consequences often with the onset of certain disease conditions (Fig. 15.1). Numerous studies implicate mitochondrial dysfunction as a fundamental factor for multiple pathologies in humans that include cardiovascular disorders, myopathies, certain cancers, type II diabetes and neurodegenerative diseases [1–12]. Neurodegenerative diseases such as Alzheimer’s and Parkinson’s (AD and PD) are particularly predominant in elderly population who have been linked with age-associated decline in mitochondrial health that leads to cellular damage [6, 8, 11, 13]. For example, several PD-associated genes interfere with pathways regulating mitochondrial function, morphology and dynami
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