The rise of mitochondria in medicine

Abstract

Once considered exclusively the cell's powerhouse, mitochondria are now recognized to perform multiple essential functions beyond energy production, impacting most areas of cell biology and medicine. Since the emergence of molecular biology and the discovery of pathogenic mitochondrial DNA defects in the 1980's, research advances have revealed a number of common human diseases which share an underlying pathogenesis involving mitochondrial dysfunction. Mitochondria undergo function-defining dynamic shape changes, communicate with each other, regulate gene expression within the nucleus, modulate synaptic transmission within the brain, release molecules that contribute to oncogenic transformation and trigger inflammatory responses systemically, and influence the regulation of complex physiological systems. Novel mitopathogenic mechanisms are thus being uncovered across a number of medical disciplines including genetics, oncology, neurology, immunology, and critical care medicine. Increasing knowledge of the bioenergetic aspects of human disease has provided new opportunities for diagnosis, therapy, prevention, and in connecting various domains of medicine. In this article, we overview specific aspects of mitochondrial biology that have contributed to - and likely will continue to enhance the progress of modern medicine.

Keywords: Brain function; Gene expression; Immunity; Medical science; Mitochondria; Mitochondrial dynamics; Signaling; mtDNA.

Figure 1

Normalized proportions of published Medline-indexed medical articles from 1980 to January 1 2016, related to various cellular components: mitochondria, nucleus, endoplasmic reticulum (ER), and Golgi apparatus. Note the increase in mitochondria-related publications following the invention of polymerase chain reaction (PCR) in 1985, the discovery of the first pathogenic mtDNA mutation/deletion in the 1988, and steady rise since the year 2000. In comparison, the number of publications about the cell nucleus has steadily decreased in the ‘post-genomic era’ following the completion of the human genome project in 2001, which demonstrated that the long searched genetic origin of common chronic diseases is likely not encoded in nuclear genes. Data for this figure was extracted from Medline/PubMed by searching the term “medicine” in combination with either “nucleus”, “mitochondri*”, “endoplasmic reticulum”, or “Golgi”.

Figure 2

Multifaceted mitochondrial pathogenesis. (A) Somatic tissues contain 100-1000's of mitochondrial DNA (mtDNA) molecules each, such that a mixture of normal and mutated copies can coexist in a state of heteroplasmy. (B) The mitochondrial genome, containing 37 genes essential to respiratory chain assembly and function. (C) MtDNA heteroplasmy for the most common pathogenic MELAS-causing m.3243A>G mutation of the tRNA^Leu(UUR) gene causes genome-wide transcriptional reprogramming; data adapted from (Picard et al., 2014b). (D) Mitochondrial signals promoting cancer initiation and progression. (E) Abnormal mitochondrial function and positioning alters multiple components of the nervous system. (F) Metabolic programming of immune cell differentiation and proliferation into anti- and pro-inflammatory phenotypes, driven by the balance of oxidative phosphorylation (OXPHOS) vs. glycolysis and mitochondrial reactive oxygen species (mtROS).

Figure 3

Multi-level organization of mitochondrial molecular composition, structures, functions, and signaling roles within the cell. These nested facets of mitochondrial functions are depicted hierarchically in a Maslow-type pyramidal fashion with the most basic determinants at the bottom and more complex and emergent elements above. These facets of mitochondria (first level) are regarded as determinants of higher-level physiological functions (second level), which in turn influence systems-level functions (third level) that contribute to clinical outcomes and mortality. Figure adapted from (Juster et al., 2011).