OPINION published: 23 September 2016 doi: 10.3389/fncel.2016.00219 Frontiers in Cellular Neuroscience | www.frontiersin.org 1 September 2016 | Volume 10 | Article 219 Edited by: Rosanna Parlato, University of Ulm, Germany Reviewed by: Jari Koistinaho, University of Eastern Finland, Finland *Correspondence: Manoj Kumar Jaiswal mj2750@cumc.columbia.edu Received: 10 June 2016 Accepted: 07 September 2016 Published: 23 September 2016 Citation: Paine A and Jaiswal MK (2016) Promise and Pitfalls of Mitochondrial Replacement for Prevention and Cure of Heritable Neurodegenerative Diseases Caused by Deleterious Mutations in Mitochondrial DNA. Front. Cell. Neurosci. 10:219. doi: 10.3389/fncel.2016.00219 Promise and Pitfalls of Mitochondrial Replacement for Prevention and Cure of Heritable Neurodegenerative Diseases Caused by Deleterious Mutations in Mitochondrial DNA Ananta Paine 1 and Manoj Kumar Jaiswal 2, 3 * 1 Division of Allergy/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA, 2 Molecular Imaging and Neuropathology Division, New York State Psychiatry Institute, Columbia University, New York, NY, USA, 3 Department of Psychiatry, Columbia University, New York, NY, USA Keywords: neurodegenerative disease, mitochondria, mitochondrial gene transfer (MGT), mitochondrial replacement techniques (MRT), mitochondrial DNA (mtDNA), mitotherapy Mitochondria are cytoplasmic organelles present in eukaryotic cells that serve as major source of cellular energy produced through oxidative phosphorylation and thus also known as the power plants of eukaryotic cells. A distinct feature of mitochondria is its capacity to regenerate owing to own set of genomic material containing 37 genes. It is now well-known that mutations in mitochondrial DNA can cause many inherited diseases including ones that affects neurons and nervous systems. Importantly, in contrast to other cells, neuron rely heavily upon mitochondria due to their inability to derive sufficient energy though glycolysis (Wallace et al., 2010). As a results mitochondrial dysfunction severely affects neuronal cells and proved to be central in the pathogenesis of many neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD) and many others (Johri and Beal, 2012). According to Friedrich Max Müller, Mitochondria’s are “Advaya” ( ) which in Sanskrit means unique and in Upanishads it means ultimate (Max Müller, 1823–1990). Mitochondria are cell’s energy factories, divide, multiply, manufacture ATP to fuel all of life’s activities. Mitochondrial DNA replacement has been successful in mice and primates and with the refinement of MRT, we hope that it becomes a reality in human. There are more than ∼700 known disease-associated mitochondrial DNA (mtDNA) mutations (mitomap.org). Up to 4000 children per year in the US are born with inherited mtDNA disorders (Schaefer et al., 2008). In recent years, major advances in the field of nuclear transfer techniques offer the possibility to transfer the nuclear material from one cells with damaged and dysfunctional mitochondria to into another cell only containing cytoplasmic material resulted from careful removal of the nuclear material before the transfer. Such transfer gives rise to cells where damaged and dysfunctional mitochondria gets replaced by healthy mitochondria from the donor cells keeping Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CRISPR/Cas, clustered regularly interspaced short palindromic repeats and CRISPR-associated; fALS, familial amyotrophic lateral sclerosis; FDA, food and drug administration; HD, Huntington’s disease; HFEA, human fertilization and embryology authority; MRT, mitochondrial replacement technique; mHTT, mhuntingtin; mtDNA, mitochondrial DNA; mSOD1, mutant superoxide dismutase 1; MNs, motor neurons; MND, motor neuron disease; MQC, mitochondrial quality control; PD, Parkinson’s disease; PINK1, PTEN- induced putative kinase 1; PBT, polar body transfer; PNT, pronuclear transfer; ROS, reactive oxygen species; ST, spindle transfer; SOD1, superoxide dismutase 1; TALENs, Transcription Activators like effector nucleases; [Ca 2+ ] i , cytosolic calcium.