Mitochondrial DNA: Prometheus’ Gift or Pandora’s Box?

Mitochondrial DNA: Prometheus’ Gift or Pandora’s Box?


>>THANK YOU FOR COMING TO THE WEDNESDAY AFTERNOON LECTURE TODAY. MARCH 21, 2012. MY NAME IS STEVE ZULLO, THE MITOCHONDRIAL INTEREST GROUP COORDINATOR AND PROGRAM DIRECTOR AT NIBIB AND IT’S MY GREAT PLEASURE TO INTRODUCE TO YOU NOT OUR SPEAKER, BUT THE DIRECTOR FOR NHLBI, BOB BALL BAN.>>THANKS AND WELCOME. FIRST ANNOUNCEMENT I WANT TO MAKE IS THAT THERE WILL BE COFFEE AND SNACKS AFTERAWARDS AND WE SHOULD THANK FAES, WHO HAS COME TO THE RESCUE OF NIH AGAIN. SO WE GREATLY APPRECIATE THAT. IT’S MY PLEASURE TO INTRODUCE DR. DIMAURO, WHO IS THE LUCY G MOSES PROFESSOR OF NEUROLOGY AT COLUMBIA. HE RECEIVED HIS Ph.D. AND EARLY TRAINING IN NEUROLOGY AT ONE OF THE GREAT MITOCHONDRIAL UNIVERSITIES IN EUROPE, AND THAT’S ATABA. I UNDERSTAND THAT’S NOT HIS REAL INTEREST AT THAT TIME. I THOUGHT THAT MIGHT HAVE BEEN THE ORIGINS OF HIS INTERESTS BUT AT THAT TIME, PEOPLE WHO KNOW HIS CAREER IT WAS ORIGINALLY IN FLYCOLYSIS. HE WENT ON TO THE UNIVERSITY OF PENNSYLVANIA WHERE HE THEN TOLD ME WHERE HE REALLY GOT INTERESTED IN MITOCHONDRIA, WHERE PROBABLY A LOT OF PEOPLE IN THIS ROOM DID, RIDICULOUS AMOUNT OF DNA COMPARED. BUT VERY IMPORTANT, AS I HOPE I CONVINCE YOU OF. BUT, IN FACT, THE STORY OF MITOCHONDRIAL DNA IS OLDER THAN THE MYTH OF PROMETHEUS. IT GOES BACK ABOUT OVER A BILLION YEARS AGO WHEN AS YOU ALL KNOW, BACTERIA WHICH WERE ABLE OF UTILIZING OXYGEN, METABOLICALLY, BECAME TO PERMANENT RESIDENT IN EARLY CELLS THAT DID NOT HAVE THAT CAPACITY. AND THIS BECAME PERMANENT AND THE BACTERIA BECAME MITOCHONDRIA AND THE REST IS HISTORY. ALTHOUGH MITOCHONDRIA HAS A MULTITUDE OF DIFFERENT FUNCTIONS, IT IS FAIR TO SAY THAT ONE OF THE MOST IMPORTANT, IF NOT THE MOST IMPORTANT IS THE PRODUCTION OF ENERGY. AND IN FACT, THEY DO PRODUCE MOST OF THEIR ENERGY FROM THE CELL. THAT’S WHY IN THIS VERY SCHEMATIC REPRESENTATION OF THE MITOCHONDRIAL, DOUBLE MEMBRANE, TWO MEMBRANES, AND SHOWING THE ORIGIN, THE FUEL THAT MITOCHONDRIA USES TO GENERATE ENERGY, MAINLY CARBOHYDRATES AND FATTY ACIDS WHICH MOSTLY DERIVED WITHIN THE MITOCHONDRIAL IN THE CYCLE ALTHOUGH THE TRANSPORT IS QUITE COMPLEX. HERE I’M SHOWING THE TERMINAL PATHWAY, THE REST DELIVERED TO A CHAIN, WHICH IS REALLY THE ENERGY GENERATING PARTY. THE BUSINESS END OF ENERGY GENERATION. OKAY, HERE IS A CLOSER VIEW OF. WHAT I WANT TO SAY IS I’M SHOWING THIS PATHWAY, THIS RESPIRATORY CHAIN NOT ONLY BECAUSE OF ITS ORIGIN IMPORTANCE BUT BECAUSE IT’S THE ONLY PATHWAY IN THE CELL WHERE TWO GENOMES ARE NEEDED FOR IT TO FUNCTION. THE NUCLEAR GENOME AND MITOCHONDRIAL GENOME AND HERE IS A CLOSER VIEW OF THE RELATIONSHIP BETWEEN THE MITOCHONDRIAL GENOME AND THE RESPIRATORY CHAIN. AND THE GENES IN THE MITOCHONDRIAL ARE COLOR ENCODED TO THE PROTEIN THAT IS THEY ENCODE. ONLY 13 PROTEINS. VERY FEW. BUT AS WE SEE, ESSENTIAL. SEVEN PROTEINS IN COMPLEX 1, NONE IN COMPLEX 2. KEEP THIS IN MIND FOR A FEW MINUTES. ONE PROTEIN IN COMPLEX 3. THREE CATALYTIC COMPLEX 4 AND TWO OF THE — (INDISCERNIBLE) — SO VERY, VERY SMALL AMOUNT OF PROTEIN. NOTICE HOW THE RESPIRATORY CHAIN ARE RESULTING IN ONE COMPLEX OR THE OTHER AND THE N-THE REDOX ENERGY GENERATED A SERIOUS REACTION AND IS PRESERVED AS — POTENTIAL. AND THEN, THIS WAY THE MITOCHONDRIAL BECOMES NEARLY CAPACTORY IF YOU WANT. AND THEN WHEN ENERGY HAS TO BE GENERATED, WELL, IT IS POTENTIALLY GENERATED OF THE RESPIRATORY CHAIN OF COMPLEX 4 FROM THE INSIDE TO THE OUTSIDE OF THE MITOCHONDRIAL MEMBRANE AND THEN THESE SAME PROTEINS FLOW BACK INTO THE MITOCHONDRIAL AT THE LEVEL OF COMPLEX 5 WHERE IT IS GENERATING ATP, WHICH I SHOW YOU IN A SECOND. I CANNOT RESIST SHOWING YOU FOR A MOMENT, FOR THE FEW SECONDS THAT THIS PRESENTATION OF THESE MAGNIFICENT, SMALLEST ROTARY MACHINE IN EXISTENCE, ATP SENGY SIS, MADE OF A REPORT — SYNTHESIS. IT LIES IN THE MITOCHONDRIAL MEMBRANE AND THE STATOR IS IN THE MATRIX. AS PRO TONS FLOW INTO THE CHANNEL OF THIS COMPLEX, THE ROTOR TURNS AT THEIR RESPECTAL SPEED OF ABOUT 1000RPM AND THIS MOVEMENT SETS IN MOTION THIS WHICH OPENS AND SLICES OF THE STARTER, ALLOWING ATP AND PI TO COME INTO THIS PORTION OF THE ATP SYNTH SAYS GENERATING ATP, WHICH IS THEN RELEASED INTO THE MATRIX. IT IS NEEDED EVERY DAY FOR ACTIVITY. IF YOU HAVE ANOTHER — A NEW DNA, NEW GENETICS. DIFFERENT OF THE MANDELIAN GENETICS, WE KNOW WE LEARNED IN COLLEGE, THAT’S MITOCHONDRIAL GENETICS, WHICH NEEDS TO BE KNOWN NOW BY PRACTICING TRADITIONS. SO MITOCHONDRIALES DIFFERS FROM NEW TRANSGENETTICS HOW? THREE MAJOR WAYS AS YOU KNOW. FIRST MATERNAL INHERITANCE. THE SAME EXACT AMOUNT OF GENETIC INFORMATION FROM FATHER AND MOTHER. NOT ALL MITOCHONDRIAL DNA — THE VERY IMPORTANT RULE IS THE HETEROPLASMY AND THE DEPRESSION EFFECT. HETEROPLASMY MEANS THAT WHILE AGAIN IN THE DNA, WE ARE DEALING WITH TWO ALLELES OF EACH GENE WITH MITOCHONDRIAL DNA, MITOCHONDRIAL. DEALING WITH HUNDREDS OR THOUSANDS OF MITOCHONDRIA IN THE CELL AND HIGHER NUMBER OF MITOCHONDRIAL DNAs BECAUSE EACH MITOCHONDRIAL GOES FROM TWO-10 COPIES OF MITOCHONDRIAL DNA. SO WE ARE — ATP IS POPULATION GENETICS, NOT MANDELIAN GENETICS. AND THE FIRST QUESTION WILL BE, WHAT WOULD BE THE CONSEQUENCE AT THE CLINICAL LEVEL OF THAT? THE CONSEQUENCE WOULD BE THAT IF YOU HAVE A MUTATION AND MITOCHONDRIAL DN A, THE PHENOTYPICS WILL DEPEND NOT JUST ON WHETHER THAT MEW STATION PRESENT BUT AT WHAT CONCENTRATION? SO IT DEPENDS ON THE ENERGY AMOUNT OF MUTANTS VERSUS WILDTYPE MITOCHONDRIAL DNA AND IT WILL BE AT A MEANING LEVEL OF MUTANT MITOCHONDRIAL DNA NEEDED FOR THE CHAIN NOT TO FUNCTION PROPERLY AND FOR THE PHENOTYPE TO APPEAR. THIS IS ALSO THRESHOLD EFFECT AND IT’S IMPORTANT THAT IT’S A RELATIVE CONCEPT. TWO DEPEND ON HIGHLY OXIDATION WITHOUT A LOWER THRESHOLD THAN THOSE WHO DEPEND LESSOR MORE ON GLYCOLYSIS IF YOU WANT. THE THIRD IMPORTANT DIFFERENCE IS MITOTIC SEGREGATION, WHICH IS SORT OF BARELY ILLUSTRATED HERE. FROM ONE GENERATION OF CELLS TO THE NEXT. THE PERCENTAGE OF MITOCHONDRIAL DNA CAN CHANGE EITHER INCREASING OR DECREASING AND THEREFORE NOT ONLY THE GENOTYPE BUT THE PHENOTYPE MAY CHANGE IN REALTIME IN THE-OF A PATIENT. AND THIS IS NOT JUST THEORY. IT’S JUST BEEN VERIFIED IN CLINICAL PRACTICE AS I MAY BE ABLE TO SHOW YOU IF I HAVE TIME. NOW YOU KNOW IT’S MITOCHONDRIA PRESENT IN EVERY TISSUE OF THE BODY. NO EXCEPTION. NOT EVEN — BECAUSE. (INDISCERNIBLE) SO MUTATIONS MITOCHONDRIAL DNA CAN AND OFTEN DO EFFECT A MULTINESS OF TISSUES. MANY ISSUES. THERE ARE SOME TISSUES POST MITOTIC TISSUES AND HIGHLY OXIDATED TISSUES THAT ARE MORE SENSITIVE TO MITOCHONDRIAL DNA MUTATIONS. THE BRAIN SKELETAL MUSCLE, HEART MUSCLE, KIDNEY, INNER EAR, AND THE RETINA AND OTHERS. SO, THAT PROVIDES THE CLINICIAN WITH A FEW RED FLAGS IF YOU WANT. AS I MENTIONED MORE AND MORE, IF YOU ARE DEALING WITH A MULTISYSTEM DISORDER, YOU HAVE TO THINK ABOUT THE POSSIBILITY OF A MITOCHONDRIAL DNA MUTATION. THAT’S NOT OBLIGATORY BUT YOU HAVE TO THINK ABOUT IT. PARTICULARLY WHEN YOU HAVE SOME TYPICAL SYNDROMES, AS I SHOW YOU LATER BUT ALSO IN ANY SUBSTITUTION. THERE ARE SOME SYMPTOMS WHICH ARE VERY COMMON IN TISSUE AND MITOCHONDRIAL DNA DISORDERS SUCH AS SHORT STATURE, HEARING LOSS, DIABETES. KEEP IN MIND THAT AS YOU SEE IN A MOMENT, BECAUSE OF INTERNAL PLASMID, VERY OFTEN IT’S NOT — AND IT WILL ONLY SHOW FLAGRANT SYMPTOMS OF MITOCHONDRIAL DISORDER WHILE THE MOTHER AND MATERNAL LINE MAY BE ONLY MILDLY OR NOT EFFECTED AT ALL. THE MOTHERS TRANSMIT TO ALL PROGENY BUT ONLY WOMEN WILL CARRY DOWN THROUGH THE DESCENDANTS AND IT WILL BE BETTER ADDS AN EXAMPLE OF PATERNAL TRANSMISSION. NOW I HAD TO SPEND A FEW MINUTES TO CONVINCE YOU OF THE IMPORTANT OF MUSCLE BIOPSY FOR MITOCHONDRIAL LINKED TO DISORDERS. THIS IS SERIOUS CROSS SECTIONS FROM THE MUSCLE BIOPSY OF THE PATIENTS WITH SYMPTOMS. I COME BACK TO THAT. MITOCHONDRIAL DNA DISORDER. THERE ARE THREE STAINS HERE. MODIFIED STAIN WHICH WAS INTRODUCED IN THE FIELD IN THE EARLY 60s. THIS ONE GIVES THE BLUE COLOR AND THE OXYGEN STAIN, THE BROWN, THAT GIVES THE BROWN COLOR. NOW YOU SEE THAT SOME FIBERS HAVE APPEALS HERE LIKE THIS FIBER. NAMELY THEY HAVE PURPLISH COLORATION. IT SIMPLY REPRESENTS A LARGER ACCUMULATION OF MITOCHONDRIA. THIS IS SEEN BETTER WITH THE HIGH JONGINOUS THEME. I REMINDED YOU WHEN I SHOW YOU THE RESPIRATORY CHAIN. IT IS THE ONLY ONE COMPLETELY ENCODED BY DNA. SO IT DOES — WHETHER OR NOT LIKE A DNA ARE EFFECTED. IT ONLY REPRESENTS OR ONLY SHOWS MITOCHONDRIA. IT’S A GOOD MARKER OF MITOCHONDRIAL MASS AND THEREFORE WHEN YOU HAVE MITOCHONDRIAL PROLIFERATION, YOU SEE THESE TWO SPREAD BLUE FIBERS. YOU SEE NO LACK OF ACTIVITY. THE FIBERS ARE COX NEGATIVE. AND THEN RECENTLY THESE APPEARED AND INTRODUCED A VERY SIMPLE METHOD, WHICH IS THE COMBINATION OF THE COX STAINING. LITERALLY OVERLAPPING THE TWO. IN NORMAL CONDITIONS, ALL YOU SEE IS THE BROWN STAIN. BUT IF YOU HAVE A SMALL DECREE, THE SDH STAIN SHINES THROUGH AS YOU SEE HERE. IT’S A WONDERFUL WAY OF REVEALING COX NEGATIVE FIBERS EVEN WHEN THEY ARE NOT VERY IMPRESSIVE. IN THIS, LESIONS OF PANDORAS BOX. WE SEE PANDORA AS A VICTIM OPENING THE BOX AND LETTING LOOSE — IT HAD TO BE TAKEN. WONDERFUL NEUROSCIENTISTS WHO HAVE MANY ACCOMPLISHMENTS IN PATIENTS WITH MYOPATHIES. THEN LATER THAT YEAR, DUG, WHO WAS THEN AT EMORY UNIVERSITY, DESCRIBED THE FIRST PHOTOGENIC MUTATION IN A LARGE AMERICAN FAMILY WITH LABOR OP TICK NEUROPATHY. THIS IS — WHICH IS VERY COMMON CAUSE OF BLINDNESS IN YOUNG ADULTS. MOSTLY MEN. TWO PAPERS WITH A TREMENDOUS RIPPLE EFFECT AND THERE WAS A FERVOR OF THE SEARCH ON MUTATIONS. YOU SEE IT PRESENTED IN THESE TWO SLIDES. THIS IS SITUATION IN 1988. SINGLE DELETION, ONE MUTATION IN 94 AND IN SUBUNITS 4 COMPLEX ONE. 2011, THERE ARE NOW OVER 2000 OR 200 MUTATION IN MITOCHONDRIAL DNA WHICH HAS BECOME VERY BUSY IN MUTATION REPRESENTING YELLOW AND BLUE TO SHOW YOU THAT THE BLUE ONE IS AFFECTED MOSTLY IN AGING — FORGOT TO TELL YOU EARLIER THAT IT DOES CONTAIN THE 13 GENES ENCODING PROTEINS. IT CONTAINS 22TRNA GENE AND TWO OTHER GENES. AND IN MUTATIONS SPECIFICALLY IN ENCODING GENES. I ACTUALLY SHOULD CORRECT THAT BECAUSE I JUST REALIZED THAT IF YOU GO TO THE MOST RECENT — THERE ARE 300 MUTATIONS. SO IT’S GETTING CRAZY. NOW IN GENETIC CLASSIFICATION AND MITOCHONDRIAL DISORDER SINCE I PROPOSED LONG AGO IS VERY SIMPLE. YOU DE– DIVIDE THE DISEASE INTUSE THOSE MUTATIONS OF MITOCHONDRIAL DNA AND THOSE — THE FACT THAT THIS AS WELL AS LONG SER DUE TO THE FACT THAT THERE ARE MORE GENES ENCODED IN DNA BUT TO THE EFFECT OF THE MITOCHONDRIAL DNA HAS BECOME — AND DEPENDS HEAVILY ON DNA FOR A NUMBER OF ESSENTIAL FUNCTIONS AND THAT’S WHY THIS LIST IS LONGER. BUT TO GO BACK TO MITOCHONDRIAL DNA, IT CAN BE DIVIDED INTO TWO FLAVORS. THOSE WITH PROTEIN SYNTHESIS IN TOTAL AND THOSE THAT EFFECT SINGLE INDIVIDUAL PROTEINS AS I SAY. SO LET’S GO TO THE FIRST GROUP. THE PROTEIN CODING GENES HAVE BEEN EITHER PROTEIN — SORRY. PROTEIN SYNTHESIS EITHER BY REARRANGEMENTS OF MITOCHONDRIAL DNA OR BY MUTATIONS IN GENES. NOW LET ME GIVE YOU QUICK EXAMPLES OF THE TWO SITUATIONS. THIS CAN CAUSE THREE PHENOTYPES. EITHER GENERALIZE VERY SEVERE PHENOTYPE, WHICH EFFECTS ESSENTIALLY ALL TISSUES BUT PARTICULARLY THE BRAIN, THE EYES, THE PIGMENTOSA. THE MUSCLES WITH — CEREBELLUM AND YOU NAME IT. IT’S A TERRIBLE DISEASE BEGINNING BEFORE AGE 20. AND HERE IS AN EXAMPLE OF WHAT OUR FIRST PATIENT, YOU SEE HOW SHORT SHE IS, INITIATED AND YOU MAY SEE THAT SHE HAS SEVERE — (INDISCERNIBLE) SHE DIED SOON AFTER THIS PICTURE WAS TAKEN. NOTICE AN EXCEPTION TO THE RULES I MENTIONED TO YOU. THE RULES OF GENETICS. THIS IS A MODEL — THIS IS HER MOTHER AND THIS IS HER SON AND THEY ARE NORMAL. SO MITOCHONDRIAL SINGLE DELETIONS ARE USUALLY NOT INHERITED AND NOT TRANSMITTED. WE CAN REALLY DISCUSS LATER. AND TWO OTHER PHENOTYPES, ONE IS A PURE MYOPATHY. IF YOU WANT — EFFECTING ONLY MUSCLE, INCLUDE SOMETHING DEGREE OF WEAKNESS AND THEN IN A DISORDER, THE SYNDROME EFFECTS — PEARSON SYNDROME CAUSING SID ROW BLASTIC ANEMIA AND SOMETIMES PARASITE PENIA AND PERITONEAL DYSFUNCTION. THE NEXT GROUP IS THE DEFECT OF TRNA. THERE ARE MANY EVER THEM. I CERTAINLY DON’T WANT TO REVIEW THEM FOR YOU. I USE MELAS AS AN EXAMPLE BECAUSE IT IS THE MOST COMMON AND MOST SEVERE DISORDERS. SO IT ALSO — IN CHILDHOOD. IT STANDS FOR CHILDHOOD AND AGAIN NOTHING VERY SPECIFIC. YOU DON’T EXPECT TO SEE IN CHILDREN OR YOUNG ADULTS AND THE SUGGESTION MIGHT — IN A PERSON YOUNGER THAN 40, EXCLUDES DATA AND EXCLUDE MOST DATA DUE TO MUTATIONS IN TRNA. HERE YOU ARE. BUT WHY 80% OF CASES ARE DUE TO THIS MUTATION. THERE ARE MANY OTHER MUTATIONS ABOUT 1000 OF THEM AND I SHOW YOU ONE VERY SOON THAT ARE ANOTHER MITOCHONDRIAL GENE CAUSING THE SAME SCENERY. STROKE EFFECT THE POSTERIOR CEREBRUM ASK LOBES AND EFFECTS CEREBRAL BLINDNESS AND CORTICAL BLINDNESS AND — (INDISCERNIBLE) IN THE BLOOD AND ALSO EVEN BETTER BY IN THE BRAIN. YOU SEE THE TWO PEAKS DOUBLE BOTH IN THE CSF IN THE VENTRICLES AND IN THE BRAIN. NOTICE AS THE MOTHER IS EFFECTED CHILD, COMPLETED CHILD ALTHOUGH DRAMATICS ALSO SHOWS PEAKS OF — SO THIS IS A GOOD BIOMARKER IF YOU ARE SETTING UP THERAPEUTIC TRIAL. LET’S COME TO THE LAST EXAMPLE OF MITOCHONDRIAL DNA PRIMARY DISORDERS ON PREPROTEIN CODING GENES. AND HERE, I HAVE TO TELL YOU WHAT I CONSIDER A SYNERGY, MITOCHONDRIAL SYNERGY. BECAUSE WE KNEW FOR A LONG TIME, TWO DISORDERS DUE TO MUTATION IN MITOCHONDRIAL PROTEIN CODING GENE, AND NAMELY WHAT I TOLD YOU ABOUT, WHICH EFFECTS THREE SUBUNITS OF COMPLEX 1, WHICH IS MATERNAL INHERITED, WHICH IS SYSTEMIC, ALTHOUGH INTERESTINGLY, WHEN YOU DO A MUSCLE BOPSY IN THIS PATIENT, YOU NEVER SEE REGULAR FIBERS. THIS DISORDER WAS ALSO DESCRIBED CALLED NEUROPATHY, ATAXIA, RETINITEIS PIGMENTOSA. THESE 24 MUTATIONS IN THE SAME SITE IN THE COMPLEX 5 AND ALSO MATERNAL INHERITED AND SYSTEMIC AND AGAIN IF YOU DO MUSCLE BIOPSY, YOU DO NOT SEE REGULAR FIBERS. WE GENERALIZE AND WE HAVE TO GENERALIZE UNTIL PROVEN WRONG. WE GENERALIZE AND CONCLUDE ALL DISORDERS DUE TO PROTEIN CODING GENE MUTATIONS WERE MATERNAL INHERITED AND SIS STEMMATIC AND WITHOUT REGULAR FIBROUS MUSCLE AND WE WERE WRONG LONG AGO. I CAN ATTEST TO THAT BECAUSE OF MY INTEREST IN BIOLOGY, WAS FOLLOWING IN THE PATIENTS AND OF COURSE YOU SEE PATIENTS WITH DEFECTS IN — (INDISCERNIBLE) THE OTHER IMPORTANT FUEL THAT MAKES SENSE BUT I ASK MYSELF, WHY DON’T YOU SEE — (INDISCERNIBLE) PROBLEMS. THAT’S WHAT ENERGY IS. IF WE HAVE ENERGY SHORTAGE, WE SHOULD SEE THAT. WE DIDN’T SEE THEM BECAUSE WE DIDN’T NOT FOR THEM, BECAUSE NUMEROUS PATIENTS SAMPLE MAKE EXCEPTIONS TO ALL THREE RULES OF MITOCHONDRIAL GENETICS. NOTICE THAT ALL THE PATIENT HAVE NO FAMILY HISTORY. THEY ARE SPORADIC. SO THE NORMAL MUTATIONS, THEY ARE NOT MULTISYSTEMIC DISORDERS BUT PURE MYOPATHIES WITH EXERCISING TOLERANCE AND BUT THEY ALL HAVE MUTATIONS IN MITOCHONDRIAL DNA AND EVEN IN COMPLEX ONE, MORE OFTEN IN COMPLEX 3 OR IN COMPLEX 4. AND WAWILL THE BIOPSY SHOW IN THIS PATIENT? HERE ARE THE REGULAR FIBERS. SHOWING YOU FIBERS ABUNDANT. THIS IS MORE SENSITIVE. NOTICE THEY ARE NOT COX NEGATIVE. THEY ARE COX POSITIVE. WHY SHOULD THEY BE COX NEGATIVE? THESE ARE MUTATIONS RELIEF. THIS IS COMPLEX 3 DEFICIENCY. NOT COMPLEX 4. SO WHEN YOU SEE MUSCLE BIOPSY, THIS SHOWS YOU A PATTERN OF BLUE OR READ FIBERS AND COX POSITIVE OR NEGATIVE FIBERS. YOU KNOW BECAUSE THE MITOCHONDRIAL DNA DISORDER, IT IS AN EXAMPLE OF INTERIOR PLASMIDS. AND A DIFFERENT SECTION LEVEL OF MUTATION AND MUTATION ALONE VARIES. SO THERE ARE A LOT OF MUTATIONS HERE AND HERE AND HERE AND VERY FEW ON THE OTHER FIBERS BUT IF YOU HAVE HIGHER OR LOWER, YOU HAVE A MUTATION ALSO. SO THIS IS A PLASMID. NOW BECAUSE THERE ARE SO MANY MUTATIONS IN MITOCHONDRIAL DNA AND BECAUSE IT IS PRONE TO SPONTANEOUS MUTATION, AFTER 1988, HOW MANY OF MY FELLOWS WOULD COME TO ME ALL EXCITED TELLING ME I FOUND ANOTHER MUTATION MITOCHONDRIAL DNA AND YOU LIKE TO CALM THEM DOWN AND SAY, HOW DO YOU KNOW IF HE IS PHOTOGENIC. AND WE DEVELOPED A SESSION BUT CHRONICAL — PATH GENISITY. THE FIRST TWO OF OBVIOUS. LIMITATION SHOULD NOT HAVE REPORTED BEFORE IN A NORMAL SUBSTANCE. IT SHOULD ALTER IN EVOLUTION AND CONCERN SIZES WHICH MEANS THE FUNCTIONING IMPORTANT SITES. USUALLY, BUT NOT ALWAYS, BUT USUALLY THERE ARE INTERPLASMID MUTATIONS AND PHOTOGENIC ONE AND THE MUTATION ALONE SHOULD CORRESPOND MORE OR LESS FOR THE CLINICAL SERENITY. EXTHEN THEY SHOULD BE FUNCTIONAL. LET ME SHOW ONE THING AT A TIME. INTERNAL PLASMID, HERE IS THE IMPORTANCE OF THE MUTATION A– MUTATIONAL LOAD. I TOLD YOU THIS CAUSES USUALLY IN ADULTS WITH NULL — (INDISCERNIBLE) IT HAS MOTHERING MUTATION LOAD. BUT IN THE SAME FAMILIES WHERE IT IS PRESENT, THERE ARE OFTEN KIDS WITH VERY SEVERE NEURODEGENERATIVE DISEASE. AN EXAMPLE OF A TYPICAL SYNDROME MRI LESIONS, SYMMETRICAL LESIONS AND THIS HAS MUCH HIGHER LEVELS OF MUTATION AROUND HL — 80 OR 90%. SO, HOW DO WE PROVE FUNCTIONAL IMPORTANCE OF MUTATION? AND THIS WAS VERY DIFFICULT TO DO UNTIL — OTHERS DESCRIBED THIS INGENIOUS METHOD TO SHOW PATHOGENICITY OF A NEW MUTATION. THAT IS, THEY TOOK A PERMANENT CELL LINE USED FOR BLASTOMA. AND THIS IS THE CELL LINE AND THEY ARE EXPOSED TO BROMIDE AND ITS OWN MITOCHONDRIAL DNA, CREATING WHAT WE CALL A ZERO CELL LINE FROM THESE GENETICS AND THEN WE SEE MUTATION JUST STUDIED. AND YOU CREATED A CYBERCYTOPLASMIC HYBRID CELL LINE WHICH WITH SIMPLE STRAT JENS, YOU CAN CREATE WITH IT A VARIABLE AMOUNT OF MUTANT MITOCHONDRIAL DNA TO 100% AND THEN YOU STUDY THIS CELL LEVEL CELL LINE AND YOU STUDY REDUCTION AND YOU CAN SHOW THAT THIS IS DEFECTIVE IN THIS FUNCTION. AND YOU CAN ALSO ESTABLISH THE THRESHOLD LEVEL. AND AT WHAT MUTATION LOAD DOES THE FUNCTION CHANGE? HOWEVER, BY THIS METHOD, MOST PLASMID MITOCHONDRIAL DNA MUTATION HAD HIGH THRESHOLD AND STEEP ONES. I HAVE TO WARN YOU THAT THERE ARE NO APPLIED DIRECTORY TO MEDICINE. IN FACT, WHEN SOME OF HIS MUTATIONS WERE STUDIED IN PATIENTS, THE MUTATIONS DOES NOT HAVE DRUGS SINCE HIGH LEVELS TO BE EVIDENT FOR FUNCTIONS. SO IT’S A WARNING SIGNAL. IT WAS INVENTED BY MY COLLEAGUE. THAT SINGLE FIBER PCR. VERY SIMPLE METHOD BUT VERY EFFECTIVE. YOU SIMPLY PLUCK, LITERALLY PLUCK FROM A CROSS SECTION, A COX NEGATIVE FIBER LIKE THIS OF RAGGED BLUE AND COX NEGATIVE OR A NORMAL FIBER IN THE COX POSITIVE FIBER AND YOU DO PCR AND YOU COMPARE THE LEVEL OF THE MUTATIONS IN THE TWO AND YOU SEE, THIS IS EXTREME EXAMPLE BECAUSE IT’S A CLEAN EXAMPLE. COX NEGATIVE FIBERS HAVE ONLY MUTANT DNA. WHICH IS AN EXTREME EXAMPLE. BUT THIS IS A VERY GOOD WAY OF SHOWING PATHOGENICITY. IN THE YEAR 2000, I WROTE A REVIEW THAT I ENTITLED MUTATIONS IN MITOCHONDRIAL DNA. I WAS SCRAPING THE BOTTOM OF THE BOTTLE. IT SEEMED TO BE TRUE AT THE TIME BECAUSE IT LOOKED UNLIKELY THAT WE WOULD ADD MORE MUTATIONS TO THE ONES THAT WE KNEW. BUT IN FACT, THERE ARE A NUMBER OF — WE ARE NOT SCRATCHING THE BOTTOM EVEN NOW. THERE ARE A NUMBER OF QUESTIONS AND NOVELTYIES. FIRST THING IS FREQUENCY. FREQUENCY OF MITOCHONDRIAL LIMITATIONS AND DISEASE ARE THEY FREQUENT DISORDERS? I’M SHOWING YOU WHERE THEY DO THE BEST EPIDEMIOLOGY CALL STUDIES. FIRST DISORDERS ARE MORE FREQUENT THAN WE THOUGHT ABOUT ONE IN 1000 OR 9000 INDIVIDUALS. AND THEN WE DID SOMETHING THAT SHOULD HAVE BEEN DONE EARLIER I THOUGHT. THESE SEQUENCE — SEQUENCING MITOCHONDRIAL DNA FROM OVER 3000 NEWBORNS COLD BLOOD, 3000 NEWBORNS IN NEW CASTLE AND WE LOOK FOR THE 10 MOST IMPORTANT MUTATION AND WE FOUND THAT 1-200 OF THESE CHILDREN DID HAVE A MUTATION. IF YOU CONSIDER THE MUTATION, 1-700. WE DON’T SEE 1-700 PATIENTS THAT MAY HAVE MUTATION. BUT THE QUESTION BECOMES, WHERE ARE THESE FREQUENT PATIENTS. 700 PATIENTS? EITHER THEY GROW HAPPILY AND LIVE THEIR LIVES WITHOUT ANY PROBLEMS BECAUSE THE MUTATIONS STAYS BELOW THE FLESH HOLD, POSSIBLE. OR THESE PATIENTS MUTATION MAY SURPASS THE THRESHOLD LEVEL MAYBE IN SOME TISSUES AND NOT OTHERS. FOR EXAMPLE, I LIKE TO REMIND YOU THAT A STUDY OF DIABETES IN JAPAN HAS REVEALED THAT 3% OF DIABETIC PATIENTS HAVE MATERNAL DIABETES DUE TO THE NEAREST MUTATION. SO THIS COULD BE TRUE FOR OTHER ORGANS AND FOR OTHER DISORDERS. I WAS ASKING ABOUT AUTISM. COULD A SUBSET OF AUTISTIC CHILDREN HAVE A MUTATION IN THE BRAIN? ANOTHER THING, MUTATIONS THAT ARE UNUSUAL IN THEIR PHENOTYPE. FOR EXAMPLE, THIS IS A PATIENT THAT WE ARE ABOUT TO PUBLISH, A 15-YEAR-OLD GIRL, SPORADIC CASE, WHO HAS A MUTATION IN THE GENE ENCODING SIGHT CHROME B. IT’S AN EXTREMELY VALUABLE GENE BUT IT IS ONLY RELATIVELY SMALL NUMBER OF THESE MUTATION. THEY NOTICE WHY SOME ARE SYSTEMIC, MAJORITY ARE CONFINED TO SKELETAL MUSCLE. THEY ARE THE ONES THAT GO IN MYOPATHY I SHOWED YOU BEFORE. THIS GIRL HAD TYPICAL SYNDROME AND YET SHE HAD MUTATION CONVINCING PATHOGENIC IN THE SITE CHROME B. THERE IS STILL WORK TO BE DONE ON NEW MUTATIONS. HAPLOTYPES. WHAT DO WE MEAN? MIGRATION FROM AFRICA AND OUR MITOCHONDRIAL, OF COURSE THE MITOCHONDRIAL HAVE BEEN CHANGING. ACCUMULATING MUTATIONS. DOUG WALLACE PROPOSED THESE GROUPS A FASCINATING THEORY THAT CERTAIN APP LOW TYPES MAY CAUSE JUST A SLIGHT COUPLING OF THE POSSIBILITY OF OXIDATION AND LEAD TO PRODUCTION OF HEAT INSTEAD OF ATP. WE STILL DON’T KNOW WHY THE MITOCHONDRIAL MUTATIONS CAUSE CERTAIN DISEASES. — (INDISCERNIBLE) THESE ARE MUTATIONS EFFECTING PROTEINS IN MITOCHONDRIAL SYNTHESIS OF THE THESE TWO ARE FED TWO DIFFERENT — AND COMPLETELY DIFFERENT. AND NO GOOD CONDITION — GOOD PHYSICIAN WOULD CONFUSE THESE WHY IS THAT? ONE POSSIBILITY WOULD BE THAT THE MUTATION IS DIFFERENT TRNAs WITH DIFFERENT CONSEQUENCES. IT’S POSSIBLE. BUT UNLIKELY BECAUSE YOU EXPECT ONLY MUTATIONS TO CAUSE p53 REDUCTION AND TO CAUSE — AT THE CLINICAL LEVEL, A SWAMP OF SYMPTOMS. AND THEY DON’T. ANOTHER POSSIBILITY, THAT WAS ENTERTAINED WAS THAT MAYBE THERE IS A SPECIAL DISTRIBUTION OF THE MUTATIONS, PARTICULARLY IN THE BRAIN, THAT WOULD EXPLAIN THE DIFFERENCES BETWEEN THE SYNDROMES. AND THEY HAVE PROVEN THAT TO BE TRUE IN MANY CASES. WHAT THEY DID WAS HISTOCHEMISTRY. — (INDISCERNIBLE) OF COMPLEX 3, WHICH IS NUCLEAR ENCODER. AND THEY COMPARE IN THE TISSUES. WE ARE SEEING EXACTLY THE — WHEN YOU COMPARE THE TWO YOU HAVE NO DOUBT THAT MANY COMMUNICATIONS IN THE PATIENT, THAT THE PROTEIN IS NOT PRESENT IN THE PATIENT AS IT IS IN THE CONTROL. SO MANY MORE MUTATIONS TO THE PATIENT, WHICH IS SPECIFICALLY EFFECTIVE ORGAN. NOW WHEN YOU LOOK AT THE BRAIN, THE BIG DIFFERENCE BETWEEN THE MITOCHONDRIA AND THE ENCODED GENE. WHEN YOU LOOK AT THE NUCLEI IN NERVE, AGAIN VERY SPECIFIC EFFECTIVE AREA OF THE BRAIN SAME DIFFERENCE. WHEN YOU SEE THE ORGANIZATION IN SOLAR PLEX US IN THE BRAIN AND YOU USE PROBES, ONE OUTSIDE OF THE DELETION AND ONE INSIDE THE SINGLE DELETION, BIG DIFFERENCE AGAIN INDICATING AN ABUNDANCE OF DELETION IN THE PATIENT COMPARED TO CONTROL. SO THAT WOULD SUGGEST THAT THERE IS A DIFFERENT DISTRIBUTION MUTATION. THIS BEGS THE QUESTION OF WHAT TELLS THE DELETION TO GO TO THE PARTICULARLY TO THE PLEX US AND THE NERVE MUTATION TO GO TO THE NUCLEI? WE DON’T KNOW. NOW, AGING IS ANOTHER ONE WE DON’T KNOW ABOUT. AGAIN, SHOWING THE SAME SLIDE AS BEFORE TO POINT OUT THAT WHILE THERE ARE PRIMARY MITOCHONDRIAL MUTATIONS, THERE ARE ALSO INDIRECT CASES. THE MITOCHONDRIAL BECAME LAZY BECAUSE OF EVOLUTION AND DEPENDS ON NEW DNA FOR ESSENTIAL FUNCTIONS LIKE REPLICATION AND LIKE TRANSCRIPTION. A GROUP OF DISORDERS THAT ARE VERY INTERESTING, GENOMIC SIGNALING. AND THIS IS JUST A SCHEME SHOWING THE NUCLEUS AND THE MITOCHONDRIAL AND SHOWING THE NUMBER OF FUNCTIONS THAT NUCLEUS CONTROLS FOR THE MITOCHONDRIAL. MITOCHONDRIAL ARE THE SLAVE OF NEUTRAL DNA. SO THERE ARE A GROUP OF DISORDERS IN COMMUNICATION DEFECT THAT REALLY SHARE THE GENETIC CHARACTERISTICS OF MANDELIAN GENETICS AND MITOCHONDRIAL GENETICS. HERE ARE SOME EXAMPLES. EXAMPLES OF MULTIPLE DELETIONS OF MITOCHONDRIAL DNA. IT PROGRESSES IN MUSCLE BIOPSIES AND LOOK AT THE MULTIPLE DELETIONS. THIS IS EXAMPLE I ALREADY SHOWED YOU OF THE PATIENT WITH THE SYNDROME AND SINGLE DELETIONS. THIS IS EXAMPLE OF DEFECTIVE REPLICATION. ONE PARTICULAR MITOCHONDRIAL DNA, THESE ARE REAL PATIENTS. ORIGINAL PATIENTS UPON WHOM DEFINED THIS NEW DISORDER DEPLETION. SO YOU COMPARE THE AMOUNT OF NUCLEAR DNA AND THE MITOCHONDRIAL DNA TO THESE PATIENTS FOR EXAMPLE, MUSCLE OR KIDNEY OR OTHER TISSUES. YOU SEE CLEARLY THERE IS A DEFECT, PROFOUND DEFECT OF MITOCHONDRIAL DNA. SO REPLICATION IS HERE. AND THIS IS NUCLEAR MANDELIAN DISORDERS. NOW, WE THOUGHT WE HAD NEATLY CLASSIFIED AS AS DEFECTIVE, QUALITATIVE DEFECT WITH MULTIPLE DELETIONS AND QUANTITATIVE EFFECT WITH DEPLETION, AND TRANSLATION. WHERE NOT SO FAST. NOT SO FAST. IN FACT, IN PART, USING EXOME SEQUENCING COMBINATION WITH OTHERS, WE FOUND RECENTLY AND WHAT THE OTHERS FOUND, THAT THERE IS NO SUCH DIFFERENTIATION. WE THOUGHT THE MITOCHONDRIAL DNA DEPLETION WOULD BE PRESENT IN OUR CHILDREN AND THE MITOCHONDRIAL DELETION WOULD BE TYPICAL OF ADULTS AND IT WOULD BE A SEPARATE GENETIC CAUSES AND AS I SHOW IF YOU THESE SLIDES, I HOPE YOU SEE TOTAL MIXTURE BECOMING MORE AND MORE BETWEEN THE TWO GROUPS. SO, THE SAME GENE THAT ENCODES DEPLETION CAN ALSO CAUSE MITOCHONDRIAL DELETIONS AND DIFFERENT PHENOTYPES. WHY IS THAT? WELL, THAT BECOMES MORE UNDERSTANDABLE WHEN WE SEE WHERE THESE GENES AND THEIR PROTEINS WORK. THEY WORK ON THE MITOCHONDRIA WHICH IS REALLY WHERE THE BUILDING BLOCKS OF DNA ARE MADE. SO IT DOESN’T SURPRISE THAT MUTATIONS COULD CAUSE EITHER DEPLETION OR IN A NAME TO THIS DELETION. AGING, THREE PORTRAIT REMNANTS TO REMIND US WE ARE ALL AGING. MANY YEARS AGO LOOKING AT THE SINGLE COMMON DELETION, 5000 OR SO DELETION IN MUSCLE. THERE ARE MANY OTHER DELETIONS THAT MAY SURPAS THE THRESHOLD AND CAUSE DAMAGE. IT’S INTERESTING THAT THIS SAME AGE IS CONSIDERED THE BEGINNING OF SARCOPENIA OF THE THE BEGINNING OF THE AGE IN WHICH WE START LOSING MUSCLE MASS. — (INDISCERNIBLE) NAKED NEXT TO THE CHAIN AND NEXT TO OXIDATIVE RADICALS. IT’S NOT TRUE IT DOESN’T HAVE ANY — RANGING RAGING AND IT WAS LAUNCHED LONG AGO BY FEDERAL PEOPLE POSTULATED A VICIOUS CYCLE SUCH THAT SOMATIC MUTATION ACCUMULATED DNA AND IMPAIRMENT OX DINATION INCREASES IN THE OXYGEN RADICALS AND THESE INDUCE MORE MUTATION IN MITOCHONDRIAL DNA. THIS IS THE MORE COMMON ONE. AND THIS WAS PROVEN IN VARIOUS TISSUES AND INDUCED THE UNUSUAL WIDTH IN AN ARTICLE ABOUT GROWING OLD AND MOST COMMON MITOCHONDRIAL DISEASE. AND THIS IS AN EXAMPLE FROM DROSOPHILA. TO SHOW AGAIN WHEN YOU DO THE SAME KIND OF STUDY, CLINICAL STUDIES I SHOWED YOU BEFORE, THAT MITOCHONDRIAL DNA ENCODED PROTEIN AND TEND TO DISAPPEAR WITH AGE IN YOUNGER INDIVIDUALS AND LOOKING AT THE BODY, SAME THING. MITOCHONDRIAL ENCODES PROTEIN. SO INDEED, WE DO ACCUMULATE MUTATIONS CERTAINLY DELETIONS. IT IS NOT QUESTIONABLE WHETHER OR NOT POINT MUTATIONS ACCUMULATE WITH AGING. THIS IS REALLY MY LAST POINT. ARE MITOCHONDRIAL DNA RELATED TO DISEASES PREVENTIBLE? WHAT DO WE MEAN BY THAT? IT’S A VERY EXCITING AREA. WE ARE JUST STARTING. YES MITOCHONDRIAL DNA FOR EXAMPLE, MUTATIONS LIKE THE ONES CAUSING MEANNESS OR NERVE, WHICH ARE INDEED VERY COMMON DISORDERS, AND INDEED, SISTERS OF THE PATIENT WHO DIED HAPPENED TO US. WE HAVE COME TO YOU SAYING I’M GETTING MARRIED AND I’M TERRIFIED OF HAVING A CHILDLIKE MY SISTER. WHAT CAN YOU DO FOR ME? WHAT WE COULD DO IS SHOWN HERE. HERE YOU HAVE A PATIENT TO DO IN-VITRO FERTILIZATION AND THEN TAKE A DONOR SITE NOT FROM THE MATERNAL RELATIVE WOMAN. YOU NUCLEATE IT AND YOU THEN TAKE THE NUCLEUS AND YOU TRANSFER INTO THE HOST OSITE OF THE THE RESULT WILL BE AN EMBRYO WHICH WILL HAVE THE NUCLEAR DNA OF THE BIOLOGICAL MOTHER AND FATHER BUT THE MITOCHONDRIAL DNA OF A DO NOR. AND THE CHILD SHOULD BE NORMAL. THIS HAS BEEN DONE IN MONKEYS. INNERGON THEY PERFECTED THE TECHNIQUE USING CELLS IN METAPHASE 2 AND USING — THIS IS A TRACKER, BUT THEY USE A DIFFERENT POLARIZE MOO CROSS COPY TO VISUALIZE THE MUSCLES AND THE NUCLEUS SPINDLE. THEN THEY ARE TAKEN OFF THE SPINDLE AND CREATED SOME CARIO BLASTS THAT FUSE THEM WITH CYTOBLASTS. AS I SHOWED YOU BEFORE, THEN DO IN-VITRO FERTILIZATION AND PLANTATION AND IT WAS BEAUTIFUL. TWIN PUPS CALLED MITOAND TRACKER, WHO WERE SHOWN TO HAVE ALMOST NO MITOCHONDRIAL DNA FROM THE MOTHER THE BIOLOGICAL MOTHER, BUT ONLY FROM THE DO NORTHIS IS NOW HAPPENING IN STUDIES THAT ARE OCCURRING FOR HUMANS. THIS HAS BEEN DONE IN NEW CASTLE. THIS SHOWS TWO POSSIBILITIES I SHOWED YOU BEFORE. YOU CAN EITHER HAVE A FERTALIZED EGG AND DO THE PROCEDURE I SHOWED YOU BEFORE OR DO THE PROCEDURE LATER. IT DOESN’T MATTER OF THE THE PROCEDURE IS THE SAME AND YOU HAVE RIGHT TO FOLLOW OF COURSE THE DEVELOPMENT OF THE FETUS. NOW, THAT HAS STILL A LOT OF ETHICAL OBJECTIONS. ALTHOUGH I FRANKLY DO NOT KNOW WHY THERE IS SUCH OBJECTION, I MUST SAY IN COLUMBIA, WE APPLIED TO DO THE SAME KIND OF RESEARCH AND WE ALSO HAVE A EXCELLENT COLLABORATION WITH OUR IN-VITRO FERTILIZATION CLINIC. AND I DON’T KNOW WHY BECAUSE THIS SAME TECHNIQUE WAS APPLIED BUT PARTIALLY IN THE SO-CALLED REJUVENATION PROCEDURE THAT WAS USING MANY IVF CLINICS WHERE AN OLDER WOMAN W.H.O. HERE, AND A — (INDISCERNIBLE) AND REPLACED WITH CYTOPLASM OF YOUNGER AGE. WHAT IS THE DIFFERENCE? THOSE BABIES WERE ALSO CYTOPLASMIC BABIES MORE THAN THESE WOULD BE. BUT THERE IS OBJECTION AND EVEN IN ENGLAND WHEN THE STUDY STARTED, A TABLOID APPEARED WITH THIS TITLE. SO THIS IS A SLIDE RECOGNIZING THIS IS THE WAY I FEEL. I BIG ORCHESTRA AND HE IS THE GUY WHO PLAYS THE TINKER BELLS. THAT’S THE WAY I FEEL WORK HAS BEEN DONE BY A LOT OF COLLABORATORS. THE APOLOGIZE THE YOUNG ONCE DID NOT FIT IN HERE. THESE ARE MY MORE TRADITIONAL COLLABORATORS. ESPECIALLY ERIC AND OTHERS. AND THE SUPPORT OF THE NICHD AND NINDS AND THE MARRIOTT MITOCHONDRIAL DISEASE FOUNDATION AND THEY RECENTLY MADE POSSIBLE A DREAM OF MINE, THE CREATION OF A CONSORTIUM OF A NORTH AMERICAN MITOCHONDRIAL DISEASE CONSORTIUM THAT NOW AS THIS NUMBER OF COLLABORATORS THERE WILL BE MORE, SOMETHING MORE ADJOINING WHERE WE WILL TRY TO HELP PATIENTS REACH AND HELP COLNEEDS MAKE CORRECTIONS AND YOU DO BIOLOGICAL HISTORIES OF DIFFERENT DISEASES AND GUIDE THERAPEUTIC TRIALS. SO THIS IS A TREMENDOUS — I’M GRATEFUL FOR THAT. FINALLY, THIS IS A GOOD ITALIAN BECAUSE TODAY IS MARCH 71 AND HAPPY SPRING. THANK YOU VERY MUCH. (APPLAUSE)>>IN POPULATION, THE MUTATION USUALLY DON’T ACCUMULATE TO VERY HIGH NUMBERS. AND IN FACT, MITOCHONDRIAL MUTATIONS THROUGH GENERATIONS, ARE NOT ACCUMULATING CATASTROPHIC MUTATIONS. SO, I WONDER HOW, IN AN INDIVIDUAL THEN, AN INDIVIDUAL MUTATION IN A MITOCHONDRIA CAN TAKE OVER AND ACHIEVE A LEVEL OF — (INDISCERNIBLE).>>THAT IS AN INTERESTING QUESTION. FOR EXAMPLE, FOR WHAT WE GOT DELETIONS, IT LOOKS LIKE THE DELETIONS HAVE A — AN ADVANTAGE. FOR EXAMPLE, CHILDREN, THE EXAMPLE I CAN GIVE YOU IS AN EXAMPLE OF SEGREGATION. CHILDREN WITH PEARSON SYNDROME, IF YOU TREAT THEM WITH THE FREQUENT — YOU WOULD DIE WITHIN A YEAR. TREAT THEM WITH TRANSFUSIONS, SOME OF THEM SURVIVE. GO THROUGH A PERIOD ONLY TRAGICALLY — (INDISCERNIBLE) HAS BEEN SHOWN THAT WHILE THE DELETION, SINGLE DELETION, IS ELIMINATED BY THE RAPIDLY DIVIDING CELL. THAT’S WHY THE ORIGIN OF THESE DISAPPEAR. IN MOST MITOTIC TISSUES TO ATTRACT THE MUTATION INCREASES. AS IF IT WAS AN ADVANTAGE, WHICH IT SEEMS TO HAVE. AND IT REACHES THE THRESHOLD LEVEL AND CAUSES — (INDISCERNIBLE) SO IT IS A STRANGE AND COUNTER INITUTATIVE PREDOMINANT BUT IT HAS BEEN OBSERVED AND DOCUMENTED AND CLEARED. NOW YOU MAY SAY I WAS DISCUSSING SOME OF THIS TODAY AND BECAUSE OF THE DELETION IS SHORT AND BIG DELETION THAT WILL MAKE THE MITOCHONDRIA SMALLER, REPLICATION WILL BE FASTER. AN INITIAL EXPERIMENT IN THESE DONE BY OTHERS, THEY COULD PROVE THAT. BUT THERE MAY BE OTHERS. THAT MAY BE ONE ADVANTAGE.>>SO I HAVE A CLINICAL QUESTION. I SEE A FIRM NUMBER OF PATIENTS WITH MITOCHONDRIAL DISEASES HERE AND ONE OF THE THINGS THAT WE RUN INTO FREQUENTLY, WE SEE A PATIENT, WE SUSPECT THAT IS MITOCHONDRIAL DISEASE CLINICALLY AND OF COURSE WE TRY TO LOOK AT THE MITOCHONDRIAL DNA AND WE MORE OFTEN THAN NOT, MORE OFTEN WILL GET A CHANGE THAT WHEN WE TRY TO LOOK IT UP, IT’S NO REPORTER THAT IS POLYMORPHISM, IT HASN’T NECESSARILY BEEN PATHOGENIC AND NOW MORE COMPLEX WITH THE DATABASE, WE STARTED TO NOTICE WE ARE SEEING PATIENTS THAT HAVE GROUPS OF TWO OR THREE MUTATIONS IN DIFFERENT GENES IN THE MITOCHONDRIAL DNA THAT ARE BEING REPORTED TOGETHER IN HEIGHTO PLASMY AND I’M TALKING ABOUT MORE THAN 99%. SO MY QUESTION TO YOU, CLINICALLY, WHAT DO YOU DO WITH THOSE PATIENTS AND WE HAVE AN VISOR.>>– (INDISCERNIBLE) WHERE YOU FIND NOT ONE MUTATION BUT MORE THAN ONE. TWO OR THREE. SEVERAL PLASMA MUTATIONS OF MITOCHONDRIAL DNA.>>THERE ARE REPORTER SNPS.>>AND THEY HAVE NOT BEEN REPORTED. BUT THEY HAVE BEEN REPORTED IN THIS DATABASE AND SO SOMEONE SOMEWHERE THESE ARE DATABASES THAT IF YOU SEE THE PATIENTS YOU CAN JUST PUT IN THERE, SO OBVIOUSLY OTHER PEOPLE ARE SEEING THE SAME GROUP OF MUTATIONS TOGETHER. YET IT’S NOT CLEAR THEY ARE PATHOGENIC YET OR NOT.>>PROBABLY, WE SEE TITLE FROM THE LITERATURE WHERE THIS IS REALLY ONE MUTATION IS PHOTOGEN — PATHOGENIC AND THE OTHERS WERE SCION NOT TO BE PATHOGENIC. YOU CAN NOT EXCLUDE THE PRESENCE OF THE — (INDISCERNIBLE) THAT IS VERY INTERESTING AND UNUSUAL PHENOMENON. I THINK YOU SHOULD, THOSE MUTATIONS ARE PATHOGENIC OR ARE SYNERGISTIC, YOU SHOULD REPORT.>>THANK YOU VERY MUCH.>>THANK YOU. (APPLAUSE) PLEASE JOIN US IN THE BACK FOR REFRESHMENTS.

1 thought on “Mitochondrial DNA: Prometheus’ Gift or Pandora’s Box?”

  1. the talk was excellent but the sound quality and the video quality are a embarrassing stain on the NIH reputation how is this possible in 2020 that college video bloggers on youtube have better sound and video quality than the NIH. if you have to, take up a collection basket in the audience and get a new camera and microphone also upload decent quality video High Definition so the slide are readable

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