Author: Gianpiero Pescarmona
Date: 14/11/2007



The whole picture

As a whole mitochondria are more similar to "spaghetti" or to a sponge than to classical cartoons.

Rizzuto Rosario, 2014

The mitochondrial calcium uniporter regulates breast cancer progression via HIF‐1α, 2016

Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes, 2016

Genome Biology

The origin and early evolution of mitochondria, 2001

The space between the internal and external membrane has a pH ranging from to according to the respiratory rate.

Factors affecting respiratory rate are:

  • NADH supply
  • Oxygen supply
  • Nutrients supply
  • Cofactors availability

Mechanism of Protons pumping

Calcium uptake

Rizzuto 2004

Filosofia del mitocondrio da vedere

Neuronal glutamate processing and transport. Glutamate is processed by the endoplasmic reticulum and Golgi apparatus in preparation for fast axonal transport, which also requires other transport proteins and mitochondria. When glutamate emerges from the "trans" face of the Golgi apparatus, it is encapsulated inside a neurosecretory vesicle, which consists of a bilipid membrane. These vesicles are transported down the axon along microtubule tracks to be deposited at the tip of the axon near the presynaptic membrane. Waves of axonal membrane depolarization would trigger the release of the glutamate into the synaptic space by exocytosis, which is exhibited by the merging of the neurosecretory vesicles with the postsynaptic membrane to free the packaged glutamate. The empty vesicle would then be recycled back to the neuronal body by retrograde transport along the microtubular tracks (adapted from [32])

Active Dendrites in Motor Neurons 2004

Which role for nuclear factors in mitochondria?

Mitochondrial Proteins

Human Mitochondrial Protein Database

They are estimated to contain between 1000 and 1500 different proteins (Pagliarini et al. 2008; Sickmann et al. 2003), which are distributed across two aqueous compartments (the matrix and intermembrane space) and an inner and outer membrane. While the vast majority of these
proteins are nuclear-encoded and thus imported from their site of synthesis in the cytosol, the remaining proteins (13 in humans) are encoded by a small mitochondrial genome (mtDNA), synthesized in the matrix, and, in many cases, assembled together with imported protein subunits into large protein complexes. Diverse functions of mitochondrial AAA+ proteins: protein activation, disaggregation, and degradation. 2010

Integral Membrane Proteins

The Inner Membrane
The inner membrane contains 5 complexes of integral membrane proteins:

* NADH dehydrogenase (Complex I)
* succinate dehydrogenase (Complex II)
* cytochrome c reductase (Complex III; also known as the cytochrome b-c1 complex)
* cytochrome c oxidase (Complex IV)
* ATP synthase (Complex V)

Mitochondrial Proteins Import

Measure of Mitochondrial Membrane Potential (D y ) with the Fluorescent Probe JC-1

Mitochondrial Proteins Expression

Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1alpha. 2006 Fulltext
Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15410-5. Epub 2006 Oct 9.

Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The "malonyl-CoA signal" is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (< or =2 h) up-regulated the expression (in skeletal muscle) of the beta-adrenergic signaling molecules, i.e., norepinephrine, beta3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator gamma coactivator 1alpha (PGC-1alpha) and estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone-cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1alpha in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.

Mitochondrial biogenesis

Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. 2010
Cell Metab. 2010 Oct 6;12(4):362-72.

  • Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals.

The Origin of Mitochondria, 2010

Comparison of mitochondia

Selective loss of mitochondrial genome can be caused by certain unsaturated fatty acids. 1983

  • Abstract
    Various unsaturated fatty acids had different effectiveness for maintaining the continued replication of functional mitochondria in an unsaturated fatty acid auxotroph of Saccharomyces cerevisiae (KD115). Certain isomers of octadecenoic acid (i.e., cis-9) and eicosatrienoic acid (i.e.,cis-8,11,14) permitted continued replication of mitochondria and provided cultures that contained only 4 to 5% cells that formed petite colonies. On the other hand, cultures grown with cis-12- or cis-13-octadecenoic acid or cis-11,14,17-eicosatrienoic acid, produced a 12- to 16-fold greater frequency of petite mutants (50-60%) after 8 to 10 generations of growth. The production of the petite mutants occurred despite adequate incorporation of these unsaturated fatty acids into cellular phospholipids and an apparently normal ability to undergo the initial steps in the induction of cellular respiration. The evidence suggests that some cellular processes necessary for continued mitochondrial replication depend on the structural features of the fatty acyl chains as well as the overall content of unsaturated fatty acids in membrane phospholipids. Impairment of that process by certain inadequate fatty acids or by an inadequate supply of a suitable fatty acid leads to a permanent loss of the mitochondrial genome from the cells of subsequent generations.
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