Mitochondria Homeostasis Pathway Suite

Mitochondria provide most of the ATP fuel for the cell, are the site of important metabolic pathways and play essential roles in calcium storage, signaling and apoptosis. As such, maintenance of mitochondria homeostasis is crucial for the proper functioning of the cell. Mitochondria are dynamic organelles that form reticular networks to assure efficient distribution of mitochondrial DNA (mtDNA) and proteins. They constantly undergo fusion and fission which, along with mitochondria transport, are the components of mitochondria dynamics. Often, fusion is followed by fission to allow segregation of mitochondria with healthy membranes from those with less than optimal membrane potential. Fission is thought to be a prerequisite for mitochondrial autophagy, known as mitophagy. Mitochondria dynamics and mitochondrial autophagy are intimately connected. Components of the fusion and transport pathways are targets of Parkin (Park2) and Pink1, essential elements of quality control (QC) in mitochondrial autophagy. Of the more than 1,500 proteins that carry out the various mitochondrial functions, only 13 are encoded in the mitochondrial genome. The pathway of mitochondrial protein import impacts on every aspect of mitochondrial function. Five pathways of protein import assure the proper delivery of nuclear-encoded protein precursors to their mitochondrial sub-compartments. The mitochondria-encoded proteins are translocated from the matrix to the mitochondria inner membrane (IMM) by a single system. All 13 mitochondria-encoded proteins are components of the electron transfer chain (ETC).  The mitochondrial genome also codes for 2 ribosomal and 22 transfer RNA genes. Mitochondrial DNA replication and transcription and the translation of the protein-coding genes are also part of mitochondria homeostasis. A stress response pathway to mtDNA depletion or accumulation of misfolded proteins promotes a mitochondria-to-nucleus signal to assure the necessary increase in the expression of genes important for proper mitochondria function. This pathway, also a component of mitochondria homeostasis, is known as the mitochondria unfolded protein response. Dysfunction of mitochondria homeostasis has been associated with a range of conditions including neurodegenerative diseases and aging.  Entries highlighted in pink represent pathways with interactive diagram pages. Pathways highlighted in orange are presented within the parent pathway page; individual components are annotated to the specific pathway term.
Mitochondrial autophagy

Mitochondria dynamics

Removal of mitochondria – mitochondrial autophagy or mitophagy - proceeds via alternative routes. One involves the Pink1-Parkin duo responding to loss of mitochondrial membrane potential and mediated via ubiquitination events. Another route involves the mitophagy receptors and responds to stresses such as hypoxia or facilitates mitochondria removal under normal physiological, developmental  conditions. Click here to explore the details of this complex system. Mitochondrial dynamics consists of fission, fusion and transport pathways.  Fission allows for segregation of mitochondria with healthy membrane potential  from those with less than optimal membranes. It also promotes mitochondrial autophagy. Fusion allows for the formation of mitochondria networks. transport assures the delivery of mitochondria to places of energy demand, of which the neural synapse have some of the highest. Both fusion and transport can be inhibited by mitophagy. Click here to explore this important network system.
Mitochondrial protein import pathway

Mitochondria perform essential cellular functions. In addition to the major function of ATP production, mitochondria are the site of fatty acid oxidation, the citric acid cycle and urea cycle, and heme and iron-sulfur cluster biosynthesis. They also provide for calcium storage and signaling and have a central role in apoptosis. Yet, only ~1% of mitochondrial proteins are encoded in the mitochondrial DNA; the remaining ~99% nuclear-encoded proteins have to be imported. As such, the mitochondrial protein import pathway impacts on every aspect of mitochondrial function. Click here to explore this complex system of five specialized import pathways.