Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

808 Chapter 14: Energy Conversion: Mitochondria and Chloroplasts
both their daughters and their sons, with the daughters but not the sons producing
children with the disease. As expected from the random nature of mitotic segregation,
the symptoms of these diseases vary greatly between different family
members—including not only the severity and age of onset, but also which tissue
is affected. There are also mitochondrial diseases that are caused by mutations
in nuclear-encoded mitochondrial proteins; these diseases are inherited in the
regular, Mendelian fashion.
The Accumulation of Mitochondrial DNA Mutations Is a
Contributor to Aging
Mitochondria are marvels of efficiency in energy conversion, and they supply the
cells of our body with a readily available source of energy in the form of ATP. But in
highly developed, long-lived animals such as ourselves, the cells in our body age
and eventually die. A factor in this inevitable process is the accumulation of deletions
and point mutations in mitochondrial DNA. Oxidative damage to the cell by
reactive oxygen species (ROS) such as H 2 O 2 , superoxide, or hydroxyl radicals also
increases with age. The mitochondrial respiratory chain is the main source of ROS
in animal cells, and animals in which mitochondrial superoxide dismutase—the
main ROS scavenger—has been knocked out, die prematurely.
The less complex DNA replication and repair systems in mitochondria mean
that accidents are corrected less efficiently. This results in a 100-fold higher occurrence
of deletions and point mutations than in nuclear DNA. Mathematical modeling
suggests that most of these mutations and lesions are acquired in childhood
or early adult life, and then proliferate by clonal expansion in later life. Due to
mitotic segregation, some cells will accumulate higher levels of faulty mitochondrial
DNA than others. Above some threshold, serious deficiencies in respiratory-chain
function will develop, producing cells that are senescent. In many organs
of the human body, senescent cells with high levels of mitochondrial DNA damage
are intermingled with normal cells, resulting in a mosaic of cells with and
without respiratory-chain deficiency.
The main role of mitochondrial fusion in cellular physiology is most likely to
ensure an even distribution of mitochondrial DNA throughout the mitochondrial
reticulum, and to prevent the accumulation of damaged DNA in one part of the
network. When the fusion machinery is defective, DNA is lost from a subset of the
mitochondria in the cell. Loss of mitochondrial DNA leads to a loss of respiratory-chain
function, and it can cause disease.
All of the considerations just discussed have suggested to some scientists that
changes in our mitochondria are major contributors to human aging. However,
there are many other processes that tend to go wrong as cells and tissues age, as
one might expect given the incredible complexity of human cell biology. Despite
intensive research, the issue remains unresolved.
Why Do Mitochondria and Chloroplasts Maintain a Costly
Separate System for DNA Transcription and Translation?
Why do mitochondria and chloroplasts require their own separate genetic systems,
when other organelles that share the same cytoplasm, such as peroxisomes
and lysosomes, do not? The question is not trivial, because maintaining a separate
genetic system is costly: more than 90 proteins—including many ribosomal
proteins, aminoacyl-tRNA synthetases, DNA polymerase, RNA polymerase, and
RNA-processing and RNA-modifying enzymes—must be encoded by nuclear
genes specifically for this purpose. Moreover, as we have seen, the mitochondrial
genetic system entails the risk of aging and disease.
A possible reason for maintaining this costly and potentially hazardous
arrangement is the highly hydrophobic nature of the nonribosomal proteins
encoded by organelle genes. This may make their production in and import from
the cytoplasm simply too difficult and energy-consuming. It is also possible that
the evolution (and eventual elimination) of the organellar genetic systems is still