Universitat Autònoma de Barcelona. Facultat de Biociències

Zurita Carpio, Alberto

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MITOCHONDRIAL DYSFUNCTION AND LONGEVITYHow does malfunction increase lifespan?Alberto Zurita Carpio, Autonomous University of Barcelona. Biomedical Sciences DegreeMitochondria are double membrane organelles found in nearly all eukaryotic cells with their ownDNA (mtDNA). Their most important function is to generate ATP via aerobic respiration, but they arealso essential in many other signalling pathways.In 1995, a Caenorhabditis elegans mutant with dysfunctional mitochondria displayed longer lifespanthan wild-type worms. Long-lived C. elegans where later called “Mit mutants” and have been thefocus of recent research.Many different groups have since then reported that mild mitochondrial distress relates to salutaryeffects and extended lifespan, from yeasts to mammals.IntroductionSearch on most common scientific data bases: consulted ISI WOK, Scope and Pubmeddata bases. Key words: (("Mitochondria"[Mesh]) AND "Aging"[Mesh]) AND"Longevity"[Mesh]Materials and methodsThe UPRmt is a mechanism by which the cell reacts to the accumulation of unfolded or misfoldedproteins within the mitochondrial matrix through the expression of mitochondrial chaperonegenes. It is activated in most Mit mutants but excessive protein import deficiency generatesReactive Oxygen Species (ROS) and triggers autophagy or even apoptosis.Cell monitors mitochondrial protein import efficiency thought the import a key protein,Activating Transcription Factor associated with Stress-1 (ATFS-1).• Normal protein import: ATFS-1 is imported to mitochondria and degraded by Lon protease• Compromised protein import: ATFS-1 accumulates on cytosol, enters the nucleus and triggersthe UPRmtMitochondrial Unfolded Protein Response (UPRmt)Mechanisms involved in Mit mutant phenotypeThe mit mutant phenotype in C.elegans• Longer livespan and increased longevity• Delayed embryonic and larval development• Small adult size• Slow muscle function• Reduced fertility and fecundityAutophagy is a conserved degradation process by which intracellular components, from solublemacromolecules to dysfunctional organelles, are degraded by the lysosome. Mitophagy,selectively targets crippled mitochondria for its degradation. Overexpression of its mainregulator, Transcription Factor HLH-30, increases lifespan of wild-type worms.Cell monitors Mitochondrial membrane potential by PINK-1, a protein similar in functionality toATFS-1.Mitochondrial autophagy (Mitophagy)Many isolated mechanism explain part of the Mit mutant phenotype. All of them haveunanswered questions, and none of them explain all Mit mutant traits. However, It seemsto be clear that a narrow equilibrium between the benefits of every mechanism and thepotential damage they can do exists.There is a need for a unified system and hypothesis that tries to converge all thesemechanisms, but until all questions and mechanisms are correctly described and answered,it is an incredibly difficult task to perform. Still, although we are still at the beginning of theresearch, the potential to explain many human mitochondrial related diseases and howaging works in organisms lies here.ConclusionsBibliographyOnly relevant references are cited below. A detailed references list is available upon request for the committee:1. Haynes, C. M., Fiorese, C. J. & Lin, Y.-F. Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-proteinresponse and beyond. Trends Cell Biol. 23, 311–8 (2013).2. Munkácsy, E. & Rea, S. L. The paradox of mitochondrial dysfunction and extended longevity. Exp. Gerontol. (2014). doi:10.1016/j.exger.2014.03.0163. Lionaki, E., Markaki, M. & Tavernarakis, N. Autophagy and ageing: insights from invertebrate model organisms. Ageing Res. Rev. 12, 413–28 (2013).Reactive Oxygen Species (ROS) signallingIt is not yet know howGCN2 HIF-1Mit Mutants C. elegans also display high levels of ROSShort-lived C. elegans produce high levels of ROSROS are a source of cell damageFigure 1. UPRmt response.Abreviations: TIM, Translocase of theInner Membrane; TOM, Translocaseof the Outer Membrane; MTS,Mitochondrial Targeting Sequence;NLS, Nuclear Localization Sequence;ATFS-1, Activating TranscriptionFactor associated with Stress-1.Adapted from Haynes et al. 2013ROS signalling defines the mechanismby which the cell reacts to free radicalscaused mostly by aerobic respiration.The mitohormesis hypothesis claimsthat low levels of ROS in fact play anactive role in longevity by triggeringsignalling cascades that are protectiveto the cell. Possible mechanisms:• General Control Non-depressible 2(GCN2). Inhibits protein translation.Reported as activated on MitMutants.• Hypoxia Inducing Factor-1 (HIF-1).Protects cell agains hypoxicconditions. Its absence abrogates lifeextension in several Mit MutantsFigure 2. GCN2 response. Abreviations: TIM,Translocase of the Inner Membrane; TOM, Translocaseof the Outer Membrane; ROS, Reactive Oxygen Species;GCN2, General Control Non-depressible 2. Adaptedfrom Haynes et al. 2013Normal Electron Transport Chain (ETC) functionalityCorrect membrane potentialPINK-1 imported to mitochondria matrix and degraded by proteasesDysfuncional ETCMembrane potential dissipatedPINK-1 accumulates on outer mitochondrial membraneInteraction with ubiquitin ligase Parking and mitophagy

Mitochondrial dysfunction and longevity : how does malfunction increase lifespan?

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Mitochondrial dysfunction and longevity : how does malfunction increase lifespan?

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