Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.

Abstract

As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.