MEDICAL BIOLOGY AND

GENETICS

MITOCHONDRIA

CHAPTER 14

Assoc. Prof. Esra ÇAĞAVİ

ecagavi@medipol.edu.tr
Office: North Campus, C Blok,1st Floor, Room 131,
International School of Medicine, IMU
Office Phone: 216-681-5354
 LEARNING OBJECTIVES

¡ Explain the mitochondrion structure, function and its role in

energy metabolism

¡ Explain the transmembrane transport mechanism of proteins

to mitochondria

¡ Define the properties of mitochondrial DNA (mtDNA) its

structure and function in health and disease

¡ Compare mtDNA with the genomic DNA

¡ Define the relationship between mtDNA in aging and relate

to clinical manifestations
Alberts • Bray • Hopkin • Johnson • Lewis • Raff • Roberts • Walter

Essential
Cell Biology
FOURTH EDITION

Chapter 14
Energy Generation in Mitochondria

Copyright © Garland Science 2014

A mitochondrion is organized into
four separate compartments

Movie 14.1
 Mitochondria Can Change Their Shape,
Location, and Number to Suit a Cell’s Needs
Mitochondria most likely evolved from
engulfed bacteria
A mitochondrion can divide like a bacterium
Mitochondria import most of their lipids, but converts
some imported lipids to cardiolipins. Cardiolipin is a
double-phospholipid that contains four fatty acids.
 ***The origins of mitochondrial RNAs and proteins

Figure 14-66 Molecular Biology of the Cell (© Garland Science 2008)

MITOCHONDRIAL FUNCTIONS

Autophagy

Pagliarini and Dixon, Trends Biochem Sci, 2006

• Cytochrome C
 Intrinsic signaling in ‘Programmed Cell Death-
APOPTOSIS’ is induced by Cytochrome-C released
from the mitochondria to the cytoplasm
Membrane Transport of Mitochondrial
Proteins from Cytoplasm
 The transport of proteins into mitochondria are
through transmembrane transport
Mito: «thread»
Chondrion: «granule»

Molecular Biology of the Cell (© Garland Science 2008)

Translocation into mitochondria depends on signal
sequences and protein translocators.
Proteins Unfold to Enter Mitochondria

Movie 15.2
Oxidative Phosphorylation
(OXPHOS)
 Cells obtain most of their energy by a membrane-
based mechanisms that use the energy provided by
food or sunlight to generate ATP
Membrane-based systems use the energy stored in an
electrochemical proton gradient to synthesize ATP
Sugars and fats are both degraded to Acetyl CoA
in mitochondria
Citric Acid Cycle Generates the High-Energy Electrons
Required for ATP Production. NADH donates its high
energy electrons to the electron transport chain.
The movement of electrons is coupled to the
pumping of protons across the inner
mitochondrial membrane.
Activated carriers generated during the citric
acid cycle power the production of ATP.
Mitochondria catalyze a major
conversion of energy
NADH transfers its electrons to Oxygen through three
large respiratory enzyme complexes. The proton
gradient then drives ATP synthesis.

Movie 14.2
Quinones carry electrons within the lipid bilayer.

.
Metals Tightly Bound to Proteins Form Versatile
Electron Carriers. The iron in a heme group can
serve as an electron acceptor.

.
 The electrochemical proton gradient across the inner
mitochondrial membrane drives ATP synthesis during oxidative
phophorylation by the membrane bound enzyme ATP synthase

Movie 14.3-14-5
THE EVOLUTION OF ENERGY-
GENERATING SYSTEM
 The earliest cells probably used fermentation to produce ATP.
Electron transport chains enabled anaerobic bacteria to use
nonfermentable molecules as their major source of energy.

Figure 14-67 Molecular Biology of the Cell (© Garland Science 2008)

Oxidative Phosphorylation Evolved in Stages

.
Some major events are believed to have occured during
the evolution of living organisms on earth. Oxygen
entered Earth’s atmosphere billions of years ago.

.
The Mitochondrial Genetics and
Its Contribution to Human
Disorders
 Mitochondria contain complete genetic systems

Figure 14-53 Molecular Biology of the Cell (© Garland Science 2008)

 The organization of human mitochondrial
genome shows that animal mitochondria
contain the simplest genetic system known

Genomic DNA= 3.2-3.4x109

mtDNA = 1.6x104

Figure 14-60 Molecular Biology of the Cell (© Garland Science 2008)

 ***The origins of mitochondrial RNAs and proteins

Figure 14-66 Molecular Biology of the Cell (© Garland Science 2008)

 HOMEWORK: Mitochondrial vs Nuclear Genome

Mitochondrial genome has

- ….......... smaller/larger number of genes

- ............. lower/higher copy number

- ............. less/more effective repair system

- ............. lower/higher mutation rates

- ............. maternally/paternally inherited

 Biological Sciences $
MtDNA is maternally inherited, BUT, there can be some exceptions…

Biparental Inheritance of Mitochondrial DNA in

Humans
Shiyu Luo, C. Alexander Valencia, Jinglan Zhang, Ni-Chung Lee, Jesse Slone, Baoheng Gui,
Xinjian Wang, Zhuo Li, Sarah Dell, Jenice Brown, Stella Maris Chen, Yin-Hsiu Chien, Wuh-Liang Hwu,
Pi-Chuan Fan, Lee-Jun Wong, Paldeep S. Atwal, and Taosheng Huang
PNAS published ahead of print November 26, 2018 https://doi.org/10.1073/pnas.1810946115
Add to Cart ($10)

Edited by Douglas C. Wallace, Children’s Hospital of Philadelphia and University of Philadelphia, Philadelphia, PA, and approved
October 29, 2018 (received for review June 26, 2018)

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Significance

The energy-producing organelle mitochondrion contains its own compact genome, which is
 mtDNA can be homoplasmic or heteroplasmic

Homoplasmy refers to a cell that has a uniform collection of mtDNA: either

completely normal mtDNA or completely mutant mtDNA.

Heteroplasmy refers to a cell can have some mitochondria that have a

mutation in the mtDNA and some that do not. The proportion of mutant mtDNA
molecules determines both the penetrance and severity of expression of some
diseases.

A unique feature of mtDNA is that, at cell

division, the mtDNA replicates and sorts
randomly among mitochondria. In turn, the
mitochondria sort randomly among daughter
cells. Therefore, in cells where heteroplasmy
is present, each daughter cell may receive
different proportions of mitochondria carrying
normal and mutant mtDNA
The intrinsic pathway of apoptosis depends on
mitochondria and release of cytochrome c
from mitochondria
 Common clinical phenotypes of
mitochondrial DNA-associated diseases
 The contribution of mitochondrial DNA to disease pathogenesis.

Boyapati RK, Tamborska A, Dorward DA and Ho GT. Advances in the understanding of

mitochondrial DNA as a pathogenic factor in inflammatory diseases [version 1]. F1000Research
2017, 6:169 (doi: 10.12688/f1000research.10397.1)
How does mitochondria
contribute to aging?
Oxygen gas, O2, which has a strong affinity for electrons,
become especially reactive as soon as it acquires a single
electron and becomes partially reduced to superoxide, O2-.
Superoxide and other reactive Oxygen species damage
DNA and cause mutations to accumulate both in
mitochondrial and genomic DNA.

Approximately 90% of the O2- generated in cells is formed

inside the mitochondrion. In order to minimize the damage
caused by reactive O2 species, mitochondria and cytoplas
use superoxide dismutase and other enzymes to neutralize
toxic O2 species. Oxidative damage driven mutations
and accumulation of reactive species may be a factor
in aging.
HOMEWORK: Read this article as supplementary
information for Chapter 14.
http://www.nature.com/scitable/topicpage/mtdna-and-mitochondrial-diseases-903#
 Next Class

For next class: Chapter 15

Intracellular Compartments and Protein
Transport