Michael Lotze

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  Innate Immune Responses to Mitochondrial Nuclear Mismatch-The Smoking Gun?
  Michael Lotze

  Mammalian cells contain hundreds to thousands of mitochondrial DNAs (mtDNA) encoding essential oxidative phosphorylation genes, and can encompass varying percentages of mutant and normal mtDNAs (heteroplasmy) associated with different clinical phenotypes. By generating a set of somatic cell cybrids harboring increasing levels of the pathogenic tRNA 3243A>G mutation [0% mutant (normal), 20-30% (autism & diabetes), 50-90% (neurodegenerative disease), and 100% (Leigh Syndrome)] and assessing changes in mtDNA and nuclear DNA (nDNA) transcriptome by RNA sequencing, Doug Wallace discovered that each clinically relevant mtDNA heteroplasmy level is associated with a unique gene expression profile. Hence, small mitochondrial physiological changes precipitate abrupt changes in cellular signal transduction and epigenomic systems resulting in distinct cellular and clinical phenotypes. Mutations in the 16.6 kilobase human mtDNA can cause a broad spectrum of multi-systemic diseases. Unlike chromosomal genes which are present in only two copies per cell, the mtDNA can be present in hundreds to thousands of copies. If a cell acquires a deleterious mtDNA mutation, this creates an intracellular mixture of mutant and normal mtDNAs, a state known as heteroplasmy. Surprisingly, relatively subtle changes in the heteroplasmic levels can have dramatic effects on a patient’s phenotype. Similarly our group at the University of Pittsburgh has shown profound metabolic changes regulated by the central nuclear protein, HMGB1, evolutionarily ancient and present in all metazoans, driving mitochondrial quality control and serving as a damage associated molecular pattern (DAMP) molecule/target when released for innate and adaptive cell immunity but also promoting autophagy (programmed cell survival) within the cytosol. Nuclear-mitochondrial mismatch can be recognized by innate immune cells but not by adaptive (T and B) cells. Innate immune cells recognize stress ligands on the target cell surface which we hypothesize are promoted in part by important oxidation of critical cysteines in HMGB1.