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The integrity of mitochondria, which are the main producers of cellular energy, is often compromised in disease and ageing. This focus highlights several aspects of the regulation of mitochondrial function and homeostasis and their links to disease and ageing. It comprises Reviews that discuss mechanisms of mitophagy, which removes damaged mitochondria, the mitochondrial unfolded protein response, which is a stress response that promotes the recovery of a functional mitochondrial network, and the recent insights into how AMPK integrates energy metabolism and mitochondrial dynamics. The focus also includes a Review of the principles underlying human mitochondrial diseases and a Comment on the progress in mitochondrial replacement therapies, which prevent mother-to-offspring disease transmission.
Mitochondrial disorders encompass a broad range of pathologies, which manifest in different tissues, with variable age of onset and symptoms. Recent findings suggest that mitochondrial stress responses, which are activated by defects in mitochondrial genome maintenance and expression, contribute to cell and systemic dysfunction, and could explain the phenotypic variability of mitochondrial disorders.
Recent studies that combine cell biology, structural and proteomic approaches have unravelled how ubiquitin is conjugated to damaged mitochondria through the PINK1–parkin pathway to promote mitophagy. The findings have revealed links between PINK1–parkin, antigen presentation and neuronal survival and have implications for the understanding of neurological disorders.
Cells activate a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) when mitochondrial integrity and function are impaired to promote their recovery. Recent insights into the regulation, mechanisms and functions of the UPRmthave uncovered important links to ageing and ageing-associated diseases.
AMP-activated protein kinase (AMPK) senses cellular energy levels and phosphorylates a variety of cellular substrates to inhibit or stimulate anabolic and catabolic processes, adjusting metabolism to energy needs. Recent studies have uncovered a crucial role of AMPK in the regulation of mitochondrial dynamics and mitophagy, further expanding its role in the control of cellular metabolism.
Mary Herbert and Doug Turnbull discuss how the transmission of pathogenic mutations in mitochondrial DNA may be prevented by reproductive techniques designed to replace the mitochondria in eggs from affected women.
Navdeep Chandel highlights a study published in 1996 that — by showing that mitochondria can release cytochromecto initiate apoptosis — changed his view of the role of mitochondria in physiology.
Basal mitophagy can occur independently of the kinase PINK1 in mammalian organisms, calling for further studies to elucidate the mechanisms of mitophagyin vivo.
Uptake of Ca2+ ions by mitochondria regulates their functions and serves to buffer Ca2+ concentrations to maintain cellular Ca2+ homeostasis. Better understanding of the mechanisms, regulation and (patho)physiology of mitochondrial Ca2+ influx and efflux offers the possibility to target mitochondrial Ca2+ machineries for therapeutic benefit.
As most mitochondrial proteins are encoded in the nucleus, mitochondrial activity requires efficient communication between the nuclear and mitochondrial genomes. This is mediated by nucleus-to-mitochondria (anterograde), mitochondria-to-nucleus (retrograde) and mitonuclear feedback signalling, as well as the integrated stress response and extracellular communication, which regulate homeostasis and, consequently, healthspan and lifespan.
Signalling from the nucleus to mitochondria (NM signalling) is crucial for regulating mitochondrial function and ageing. It is initiated by nuclear DNA damage and controls genomic and mitochondrial integrity. Pharmacological modulation of NM signalling holds promise for improving lifespan and healthspan.
Sirtuins are NAD+-dependent protein deacylases that can reverse various aspects of ageing in model organisms. Trials in non-human primates and humans indicate that sirtuin-activating compounds (STACs) and NAD+precursors are safe and effective in treating inflammatory and metabolic disorders, thereby holding great potential to treat various diseases and to extend lifespan in humans.