Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. Clearance of damaged mitochondria occurs through a process called mitophagy and is critical for maintaining proper cellular functions in the body. On the one hand, mitophagy is involved in general mitochondria quality control and results in the removal of mitochondria that are damaged in conditions of cellular stress, for example when cells respond to environmental stressors such as exposure to toxins or extreme temperature changes. On the other hand, mitophagy is involved in the physiological removal of mitochondria in red blood cells during their formation, as well as in sperm–oocytes after fertilization, or physiological adaptation to hypoxia. When the process of mitophagy is disrupted, dysfunctional mitochondria accumulate and this causes disease. This is the case in some neurodegenerative conditions, such as Parkinson’s, as well as in cardiomyopathies, cancer and metabolic disorders such as type 2 diabetes.
Research conducted by the Zaccolo laboratory has identified a novel mechanism that regulates mitophagy. This mechanism involves the second messenger 3’-5’ cyclic adenosine monophosphate (cAMP) and the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). In their study, the team demonstrate that PDE2A2 is part of a mitochondrial ‘signalosome’, a multiprotein complex localised at the mitochondria inner membrane, where cAMP-dependent activation of PKA mediates the phosphorylation of MICOS (mitochondrial contact site and organising system) and subsequently modulates Parkin recruitment to the mitochondria and mitophagy. PDEA2A2, by degrading locally cAMP, modulates this process, providing a potential target for pharmacological modulation of mitophagy. The team also demonstrated that inhibition of PDEA2A2 promotes ‘browning’ of white adipocytes, a process that is known to enhance thermogenesis at the expense of fat accumulation and is characterised by accumulation of mitochondria and reduced mitophagy. Professor Zaccolo said: “These are exciting findings. ‘Browning’ of white adipocytes has been shown to reduce diet-induced obesity in animal models and the discovery that PDE2A2, an enzyme that can be targeted pharmacologically, is involved in this process offers a potential novel therapeutic approach to control metabolic disorders.”
Two Oxford medical students, Samuel Pace and Natasha Larcom, now in their 6th and 5th year respectively, were involved in the research, enabling them to secure strong technical skills as part of their career development. Samuel said: “Working with Dr Zaccolo’s group provided an excellent insight into cellular research techniques and I learnt so much from working in the group’s lab. These are skills I hope to take into any future research pursuits.” For Natasha: "It was a privilege to be part of the group and contribute to this study. I not only developed my laboratory skills, but also a more critical approach to research. This has been invaluable in my clinical studies, particularly with respect to evidence-based medicine.
The full publication, first authored by DPhil student Miguel J Lobo, "Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy" is available to read in Communications Biology.