Mitochondria are often called the powerhouses of the cell, responsible for generating most of the cell’s energy. To perform this function, mitochondria require a specific set of proteins, and the process of building them is called translation. While most protein synthesis occurs in the cytoplasm, a separate translation system operates inside the mitochondria. This internal system is dedicated to producing a small group of proteins encoded within the mitochondria’s own genetic material, highlighting a fundamental division of labor within the cell.
The Unique Machinery of Mitochondrial Translation
Central to mitochondrial translation is mitochondrial DNA (mtDNA), a small, circular genome that, in humans, contains 37 genes. Unlike nuclear DNA inherited from both parents, mtDNA is inherited almost exclusively from the mother. These 37 genes provide the blueprints for 13 proteins, 22 transfer RNAs (tRNAs), and two ribosomal RNAs (rRNAs).
This genetic information is read and translated by mitochondrial ribosomes, or “mitoribosomes.” Although they perform the same function as their cytoplasmic counterparts, mitoribosomes are structurally distinct. Mammalian mitoribosomes are composed of a small 28S subunit and a large 39S subunit, which contain the two rRNAs encoded by mtDNA and numerous proteins imported from the cytoplasm.
Completing the machinery are the mitochondrial transfer RNAs (mt-tRNAs), also encoded by mtDNA. There are 22 distinct mt-tRNAs, each tasked with recognizing specific three-letter “words,” or codons, in messenger RNA (mRNA) and delivering the corresponding amino acid to the mitoribosome. The structure of these mt-tRNAs can be more varied and sometimes truncated compared to their cytosolic cousins.
Key Differences from Cytosolic Translation
Translation within mitochondria differs markedly from the process in the cytoplasm, reflecting a different evolutionary origin that more closely resembles bacterial protein synthesis. The differences span from the genetic code to the molecules that carry out the process.
A primary distinction lies in the genetic code, as mitochondria employ a slightly altered version of the universal code. For instance, the codon UGA, which normally signals the termination of translation, instead instructs the ribosome to add the amino acid tryptophan. Similarly, the codon AUA codes for isoleucine in the cytoplasm but specifies methionine in the mitochondria.
The initiation of protein synthesis also differs. While cytoplasmic translation begins with methionine, mitochondrial translation begins with a modified version called N-formylmethionine, mirroring its prokaryotic ancestry. This process is directed by specialized initiation factors that help assemble the mitoribosome at the start of the mRNA sequence.
The structure of mitochondrial messenger RNA (mt-mRNA) is another point of divergence. Cytosolic mRNAs feature a protective 5′ cap and untranslated regions (UTRs). Most human mt-mRNAs lack these features, with the “start” codon often positioned at the beginning of the molecule. Many mt-mRNAs are also produced as part of a long transcript that is later cut to release individual protein-coding sequences.
The Role in Cellular Energy Production
Mitochondrial translation is dedicated to synthesizing 13 proteins that are core components of the oxidative phosphorylation (OXPHOS) system. This system, located on the inner mitochondrial membrane, is the cell’s main engine for producing adenosine triphosphate (ATP), the universal energy currency.
These 13 proteins are subunits of four of the five large protein complexes that make up the electron transport chain (ETC) and ATP synthase. They are components of Complex I (NADH dehydrogenase), Complex III (cytochrome b), Complex IV (cytochrome c oxidase), and Complex V (ATP synthase). The ETC works by passing electrons through these complexes, creating a proton gradient that powers ATP synthase to produce vast quantities of ATP.
Without the on-site production of these 13 proteins, the OXPHOS machinery cannot be assembled or maintained. While most proteins for these complexes are encoded in the nucleus and imported, the few synthesized locally are required for function. This arrangement highlights a coordinated partnership between the nuclear and mitochondrial genomes to sustain cellular energy.
Impact of Dysfunctional Mitochondrial Translation
When mitochondrial translation falters, it can lead to debilitating conditions known as mitochondrial diseases. These disorders arise from mutations that disrupt the synthesis of OXPHOS proteins, impairing the cell’s ability to produce energy. The mutations can occur in mtDNA, affecting mt-mRNAs or mt-tRNAs, or in nuclear DNA that encodes components imported into the mitochondrion.
Defects in mt-tRNA genes are a frequent cause of these diseases. Two examples are MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (Myoclonic epilepsy with ragged-red fibers). In approximately 80% of individuals with MELAS, the cause is a point mutation in the gene for mt-tRNA-Leu. This defect impairs the tRNA’s ability to read its codon, leading to faulty protein synthesis and symptoms like muscle weakness, seizures, and stroke-like events.
Similarly, over 80% of MERRF cases are caused by a mutation in the gene for mt-tRNA-Lys. This mutation disrupts protein synthesis, leading to symptoms like uncontrolled muscle jerks (myoclonus), epilepsy, and “ragged-red fibers” in muscle biopsies. Because tissues like the brain, muscles, and heart have high energy demands, they are often the most severely affected by these defects.