Iyer 2012 Abstract Bioblast

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Iyer S (2012) Gentle Science in the real world of mitochondrial physiology and genetics. Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Iyer S (2012)

Event: Bioblast 2012

Shilpa Iyer

The business of science is often a rat-race as we are searching for solutions in isolated closed environments, with the goal of reaching the top in our respective research fields. But, as Mahatma Gandhi said,There is more to life than increasing its speed; and In a gentle way, we can shape the world. When we apply these guiding principles to our research endeavors towards generating solutions for incurable diseases, it leads to open research environments which could eventually become more collaborative, more global, and gently shape the world. Thus, Gentle Science aims to create a bridge between science and spirituality to better understand our own lives and to live in harmony within ourselves and with the universe around us. It is important that we practice the tenets of Gentle Science in the real world of mitochondrial physiology and genetic disorders. Our Gentle Science [1] approaches have been enriched by our interactions with educators, scientists, clinicians, entrepreneurs and the patient community suffering from incurable mitochondrial disorders.

Many of these disorders represent a large group of diseases with heterogeneous clinical and pathological expressions characterized by irrevocable damage and improper functions of specialized metabolically active cell types. Examples include classical mitochondriopathies, Leber’s hereditary Optic Neuropathy (LHON), Leigh’s syndrome (LS), Amyotrophic Lateral Sclerosis (ALS), Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) syndrome, that affect children and adults. Mitochondrial DNA (MtDNA) mutations and deletions are often found in these disorders and contribute to a decline in mitochondrial energy function and diminished vigor in these disorders.

We have developed a novel approach that uses a recombinant mitochondrial transcription factor A protein (rhTFAM) for external manipulation of the mitochondrial genome present inside cells. In the context of developing relevant cell-based models for targeted drug discovery, we have used this approach to introduce, replicate, and transcribe pathogenic mtDNA in human neural progenitor stem cells, while maintaining multipotency and successful differentiation into neuronal lineage in the short term [2]. In parallel, we also used healthy mtDNA complexed with rhTFAM to transduce into the mitochondria of two classic mitochondrial diseases, as cell models for proof-of-principle studies toward conducting mitochondrial gene therapy in the future. We introduced healthy mtDNA first into the cytoplasmic hybrid (cybrid) cells containing platelets from an LHON patient and, subsequently, into primary skin fibroblasts obtained from an LS patient [3]. We showed that using healthy donor mtDNA circles complexed with rhTFAM improved respiration (Figure 1) and biogenesis in LS and LHON disease cell lines caused by different pathogenic mtDNA point mutations. Results from these ongoing studies will contribute to (a) patient- and cell- specific stem cell models for drug testing and (b) therapeutic approaches for improving respiration in patients suffering from these incurable mitochondrial disorders.

Mitochondrial disorders, Stem Cells, Protofection, Respiration, Gentle Science MiPNetLab: US VA Richmond Iyer S


Labels: MiParea: Respiration, mtDNA;mt-genetics, Genetic knockout;overexpression, mt-Medicine, mt-Awareness Mammal;model: Human  Cell line: Fibroblast Preparation: Intact cells Pathology: Inherited HRR: Oxygraph-2k 



Affiliations and author contributions

Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, USA; Email: siyer@vcu.edu

References

  1. Iyer S, Xiao E, Alsayegh K, Eroshenko N, Riggs MJ, Bennett JP Jr, Rao RR (2012) Mitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors. Gene Ther 19: 469-475.
  2. Iyer S, Bergquist K, Young K, Gnaiger E, Rao RR, Bennett JP Jr (2012) Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber's hereditary optic neuropathy and T8993G Leigh's syndrome cells. Hum Gene Ther 23: 647-6579.

Figure 1

Iyer HGT Figure6b.jpg

Mitochondrial gene therapy improves respiration in Leigh's patient fibroblasts carrying T8993G mutation (see Iyer et al., Human Gene Therapy, 2012 for details).

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