Last week I headed to Washington DC (specifically Bethesda, Maryland) for the United Mitochondrial Disease Foundation Symposium. This is the first symposium I have attended about Mitochondrial disease in an effort to find more answers for our daughter who is suspected to have this disorder. In my “other life” I wore the hat of a chemist, and thus I decided to fly in early to sit in on some of scientific meetings which began ahead of the family meetings.
The chairperson of the meeting, Vamsi Mootha, MD, kicked off the meeting with the first “ceremonial” talk. I have followed his lab through a number of articles (like this one) that have been posted on some of the online mitochondrial parent support groups I am part of. He spoke specifically about Calcium signaling and while I will not go into all the specifics of the science… the main idea was that this “uniporter” was discovered nearly 50 years ago but it was just recently that Dr. Mootha’s lab identified the subunits of the uniporter including CCDC109A/MCU. He spoke of RU360 being a potent inhibitor of Calcium uptake.
Next up was Dr. Michael Gray from Dalhousie University, and whom I shared a Supershuttle ride to the conference center with. He spoke about the evolutionary aspects of the mitochondria in other organisms specifically the reclinomonus americana, the most gene rich eubacteria like mitochondrial genome to date, that lives at the bottom of lakes and rivers.
Dr. Vaidya of Drexel University spoke next about the Mitochondrion of the malaria Parasite. He gave som interesting stats on malaria- 300-500 million contract it each year, 1 million die each year from it from 105 countries, nearly 150 species of malaria parasites (many of which are drug resistant). In the USA there were about 1700 cases in 2010 resulting in 9 fatalities and about 176 severe cases (according to MMWR, CDC). Antimalaria drugs work through the inhibition of the electron transfer chain, cplx III inthe malaria parasite (but according to Dr. Vaidya, no human cplx III).
Seven abstract presentations were given next. Here are the highlyights of one I found particularly interesting. Leonardo Alves gave a talk about Leber’s Hereditary Optic Neuropathy (LHON) associated mutation 3394 being a high-altitude adaptive polymorphism. The reason I enjoyed this talk so much was that it was the first talk of the day where I felt there was emphasis given on ENVIRONMENTAL FACTORS influencing Genomics or Proteomics! Basically in Leonardo’s talk he explained how the 3394C mtDNA mutation is found in Tibet and increases in frequency as elevation increases, but does not appear to cause disease in Tibet. He concludes, ” Hence, the 3394C variant can either be deleterious or beneficial depending on its (haplogroup) and ENVIRONMENTAL context. Thus this mtDNA variant fulfills the criteria for a common variant that PREDISPOSES to a “complex” disease.”
After lunch, the next speaker was Dr. Anu Suomalainen Wartiovaara who gave some patient case studies involving the FGF21. She described 2 families where FGF21 was crucial in the diagnosis. Family #1 had history of infertility, normal pregnancy once pregnant, myclonic jerks, liver (elevation of iron and copper), 1st child died at 8mo, 2nd child died at 21 mo, found COMPLEX 4 was LOW IN THE BRAIN…but NORMAL in the MUSCLE BIOPSY. In family 2, there was a normal pregnancy and birth, at 6months old the child had an infaction (otis) and sudden death at 7mo in the ER. Complex 4 deficiency was found int he muscle and heart. A 13 year old of the same family has selective mutism and cardiomyopathy. FGF21 may be able to be used as a biomarker in lieu of muscle biopsy since it was elevated in these scenarios. This work is published here.
Dr. David Pagliarini from the University of Wisconsin, Madison spoke about a mouse model their lab has made using lean and obese(leptin deficient) mice. They looked at obesity linked insulin resistance and type 2 diabetes between the 2 groups. They found that phosphorlation was a novel mechanism for regulating ketogenesis (the mito production of Beta -hydroxybuterate and acetoacetates, alternative fuel when glucose is limited). of particular interest is the Hmgcs2.
Dr. Jennifer Van Eyk of Johns Hopkins University, was the final presenter for the scientific session day 1, and spoke about cardiac resynchronization therapy and how mitochondrial defects and ATP production are modified after heart failure. One of her discoveries involved Cys 294 or alpha subunit of ATP synthase, which can switch from being involved in a di-sulfide bond or S-glutathionylated with heart failure to S-nitrosylation (a protective state) when resynchronization therapy occurrs.
Three more abstract presentations were done with a very interesting “rapid breath test for IN Vivo determination of Human Pyruvate Dehydrogenase Complex activity” by Dr. Stacpoole of University of Florida College off Medicine.
After this Looong day of science, and many a flash back to my chemistry grad school days at UCLA, I headed to the poster sessions and chatted for a long while with Dr. Niyazov from Ochsner Children’s Health Center in New Orleans, LA. He had a wonderful poster on “Diagnosis and Treatment of Secondary Mitochondrial Disease”. The longer I stood there and talked with Dr. Niyazov, the more I realized the PASSION he has for his patients and how he was truly a doctor who “got it” from the caregiver’s and parent’s perspective. He shared with me recordings of the “baby steps” that his patients had made on vitamin and supplementation protocols. I was right there cheering as I realized that small, incremental steps of improvement are truly what all of us parents onthis journey cling to…and this Doctor was clinging to those successes too… trying his hardest to string together more and more “baby steps” into LEAPS for mito! He was not caught up in the primary versus secondary mito debate of which came first the chicken or the egg, or what was causing the mito, a genetic diagnosis or another disease, instead he chose to treat these kids and attempt (successfully) to improve the quality of life of these kids and their families. He and I also had a nice chat about autism, vaccines, and mito. Here is a great presentation that Dr. Niyazov did on Autism and Mitochondrial Disease.
So after a briefing by the UMDF about what to say and do at the “DAY on the HILL” and some dinner at the hotel’s lounge, I turned in early… tomorrow would be an even longer day advocating on Capitol Hill for Mitochondrial Disease Awareness and Cures! Busses leave at 7:30am, SHARP!