International Journal of Molecular Sciences Review Intimate Relations—Mitochondria and Ageing Michael Webb and Dionisia P. Sideris * Mitobridge Inc., an Astellas Company, 1030 Massachusetts Ave, Cambridge, MA 02138, USA; [email protected] * Correspondence: [email protected] Received: 29 August 2020; Accepted: 6 October 2020; Published: 14 October 2020 Abstract: Mitochondrial dysfunction is associated with ageing, but the detailed causal relationship between the two is still unclear. Wereview the major phenomenological manifestations of mitochondrial age-related dysfunction including biochemical, regulatory and energetic features. We conclude that the complexity of these processes and their inter-relationships are still not fully understood and at this point it seems unlikely that a single linear cause and effect relationship between any specific aspect of mitochondrial biology and ageing can be established in either direction. Keywords: mitochondria; ageing; energetics; ROS; gene regulation 1. Introduction The last two decades have witnessed a dramatic transformation in our view of mitochondria, their basic biology and functions. While still regarded as functioning primarily as the eukaryotic cell’s generator of energy in the form of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (reduced form; NADH), mitochondria are now recognized as having a plethora of functions, including control of apoptosis, regulation of calcium, forming a signaling hub and the synthesis of various bioactive molecules. Their biochemical functions beyond ATP supply include biosynthesis of lipids and amino acids, formation of iron sulphur complexes and some stages of haem biosynthesis and the urea cycle. They exist as a dynamic network of organelles that under normal circumstances undergo a constant series of fission and fusion events in which structural, functional and encoding (mtDNA) elements are subject to redistribution throughout the network. These processes are intimately linked to the health of the mitochondrion and it would not be an exaggeration to state that the health of the cell is a reflection of the health of its mitochondria. The endosymbiotic hypothesis for the origin of mitochondria from aerobic bacteria engulfed by the primitive eukaryotic cell was originally proposed by Sagan [1] and has now gained general support. During their 1.45 billion years of co-evolution, most of the endosymbiont’s genes have been transferred to the nucleus of the host cell and of the approximately 1500 proteins that constitute the mitochondrial proteome, only a minority are encoded by mtDNA. In mammals mtDNA encodes 13 proteins of the electron transport chain, 22 mitochondrial specific tRNAs and two ribosomal RNAs. This distribution of genes across two genomes clearly implies a co-ordinate regulation of the activities of nuclear and mitochondrial genes [2]. Mutations in mitochondrial DNA are causative of several disorders with specific clinical manifestations and declining mitochondrial function, reflected in defects in ATP synthesis and increased generation of toxic reactive oxygen species is a universal feature of natural ageing. It accompanies the other hallmarks of ageing which include progressive loss of function in multiple organs, sarcopenia and increasing maladaptive low-grade inflammation. These end in death, which is a cumulative result of loss of function, leading to either increased vulnerability to environmental hazards such as predation and disease or to failure of critical organ systems such as the heart, liver or kidney. Several processes Int. J. Mol. Sci. 2020, 21, 7580; doi:10.3390/ijms21207580 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7580 2 of 50 that may contribute mechanistically to age related degeneration have been identified, including oxidative damage, accumulation of toxic protein aggregates, autoinflammatory processes, loss of stem cell populations and an increasing load of malfunctional senescent cells. Are these processes linked to declining mitochondrial function and if so, is there a cause and effect relationship? if so, in which direction does it operate? MitochondriaInt. J. Mol. Sci.generate 2020, 21, x FOR reactive PEER REVIEW oxygen species (ROS) as a consequence of the electron2 of 48 transport that drives oxidative ATP synthesis. These have a dual aspect, functioning at low levels as an important or kidney. Several processes that may contribute mechanistically to age related degeneration have communication system regulating multiple cellular responses but also directly damaging macromolecules been identified, including oxidative damage, accumulation of toxic protein aggregates, to a degreeautoinflammatory proportional to processes, their proximity loss of stem to high cell populations ROS concentrations. and an increasing Thus, loadmitochondrial of malfunctional components, proteins, lipidssenescent and cells. carbohydrates, Are these processes are linked all subjectto declining to mitochondrial accumulating function ROS and damage if so, is there which a impairs mitochondrialcause and function. effect relationship? This impairment if so, in which of direction function does by it operate? damaged molecules is reduced by two Mitochondria generate reactive oxygen species (ROS) as a consequence of the electron transport mechanisms,that (1)drives their oxidative redistribution ATP synthesis. and dilutionThese have by a thedual same aspect, fission functioning/fusion at low process levels that as an distributes newly synthesizedimportant communication components andsystem (2) regulating the selective multiple elimination cellular responses of mitochondria but also directly which damaging have acquired sufficient damagemacromolecules by a macroautophagic to a degree proportional process to thei knownr proximity as mitophagy. to high ROS concentrations. Thus, Mitochondrialmitochondrial quality components, is proteins, therefore lipids maintained and carbohydrates, by are the all subject linked to accumulating process of ROS biogenesis, damage which impairs mitochondrial function. This impairment of function by damaged molecules dynamic fissionis reduced/fusion by two and mechanisms, mitophagy (1) their and redistributi their importanceon and dilution is indicatedby the same byfission/fusion the fact thatprocess impairment of any of themthat distributes is associated newly withsynthesized poor cellcomponents function and and (2) the viability. selective Theseelimination processes of mitochondria operate in a time scale of minuteswhich have to hours acquired and sufficient yet mitochondrial damage by a macroautophagic function nevertheless process known declines as mitophagy. over decades with age. 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However, as unicellularSimpler eukaryotes (yeast) such and as largely yeast post-mitoticand C. elegans (haveC. elegans been )invaluable organisms, in unraveling they cannot the represent molecular details of mitochondrial biology, such as dynamics and the mitochondrial unfolded the complexityprotein of response. the mammal, However, with as unicellular its differentiated (yeast) and celllargely types post-mitotic and organ (C. elegans systems,) organisms, homeothermy they and mix of mitoticcannot and represent post mitoticthe complexity cells. of We the willmammal, therefore with its refer differentiated to results cell from types simplerand organ organismssystems, where germane buthomeothermy focus most and mix of the of mitotic discussion and post on mitotic data cells. from We will mammals. therefore refer We to will results consider from simpler here only the processes andorganisms mechanisms where germane relating but naturalfocus most ageing of the discussion to mitochondria on data from and mammals. interventions We will toconsider extend lifespan here only the processes and mechanisms relating natural ageing