Keynote Message
Understanding the basis of ageing to slow its course is one of the great biomedical challenges for our times. Age is the most important risk factor for most of the common mammalian diseases. Although our knowledge of the ageing process remains elusive, there is consensus that the process starts with molecular damage, leading to cell, tissue, and ultimately organ dysfunction.1
Mitochondria that are the principal source of intracellular reactive oxygen species (ROS), are thought to play a central role in this as encrypted by the free radical theory of ageing. However, the importance of mitochondrial ROS in driving ageing is met by other facets of mitochondrial dysfunction playing a critical role in cellular and organismal aging such as loss of their quality control.2
Age-associated loss of function is well established in kidney, mostly underlined by mitochondrial defects, thus making this the ideal model organ to inform ageing both at molecular and systemic level. Still relatively little is known about the properties of mitochondria in different parts of the kidney,3 demanding further investigations to inform the pathophysiology of the organ over time. Adopting in vivo and in vitro approaches, we discovered differences in mitochondrial function along the nephron, framed by different metabolism and how these dictate pattern of renal injuries.
This talk will initially report the alternative metabolic features, means of reactive oxygen species (ROS) regulation, scavenging mechanisms and loss of cell quality in kidney cells. The role played by the endogenous regulator of the mitochondrial F1Fo-ATPsynthase, IF1,4 will then be described, which contributes to the homeostasis of nephron sections and therefore represents a novel therapeutic target in both chronic and acute conditions5.
The ageing kidney model as a paradigm for animal ageing will then be considered and the contribution by key determinants of mitochondrial function and structure analysed.
Key References
1. Payne BAI, Chinnery PF. Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochim Biophys Acta. 2015;1847:1347–1353.
2. Hall AM, Campanella M, Loesch A, Duchen MR, Unwin RJ. Albumin uptake in OK cells exposed to rotenone: a model for studying the effects of mitochondrial dysfunction on endocytosis in the proximal tubule? Nephron Physiol. 2010;115:9–19.
3. Campanella M, Klionsky DJ. Keeping the engine clean: a mitophagy task for cellular physiology. Autophagy. 2013;9:1647.
4. Campanella M, Parker N, Tan CH, Hall AM, Duchen MR. IF1: setting the pace of the F1Fo-ATP synthase. Trends Biochem Sci. 2009; 34:343–50.
5. Faccenda D, Nakamura J, Gorini G, Dhoot GK, Piacentini M, Yoshida M, Campanella M. Control of mitochondrial remodeling by the ATPase inhibitory factor 1 unveils a pro-survival relay via OPA1. Cell Rep. 2017;18:1869–1883.