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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nat Cell Biol. Author manuscript; available in PMC Oct 15, 2009.
Published in final edited form as:
Nat Cell Biol. Sep 2008; 10(9): 1090–1097.
PMCID: PMC2762220
NIHMSID: NIHMS144912

Reduced Cytosolic Protein Synthesis Suppresses Mitochondrial Degeneration

Abstract

Mitochondrial function degenerates during aging and in aging-related neuromuscular degenerative diseases, which leads to the physiological decline of the cell1. Factors that can delay the degenerative process are actively sought after. Here, we show that reduced cytosolic protein synthesis is a robust cellular strategy that suppresses aging-related mitochondrial degeneration. We modelled the adult-or later-onset degenerative disease, autosomal dominant Progressive External Ophthalmoplegia (adPEO), by introducing the A128P mutation into the yeast adenine nucleotide translocase, Aac2p. The aac2A128P allele dominantly induces aging-dependent mitochondrial degeneration and phenotypically tractable degenerative cell death independent of its ADP/ATP exchange activity. Mitochondrial degeneration is suppressed by lifespan-extending nutritional interventions and by 8 longevity mutations, which are all known to reduce cytosolic protein synthesis. These longevity interventions also independently suppress aging-related mitochondrial degeneration in the pro-aging prohibitin mutants. The aac2A128P mutant has reduced mitochondrial membrane potential (Δψm) and is synthetically lethal to low Δψm conditions, including the loss of prohibitin. Mitochondrial degeneration is accelerated by defects in protein turnover on the inner membrane and is suppressed by cycloheximide, a specific inhibitor of cytosolic ribosomes. Reduced cytosolic protein synthesis suppresses membrane depolarization and defects in mitochondrial gene expression in aac2A128P cells. Our finding thus provides a link between protein homeostasis (proteostasis), cellular bioenergetics and mitochondrial maintenance during aging.

Autosomal dominant Progressive External Ophthalmoplegia (adPEO) is a neuromuscular degenerative disease clinically manifested by ptosis, progressive muscle weakness, sensory ataxia, peripheral neuropathy and parkinsonism2. Phenotypically, it is characterised by multiple deletions in mitochondrial DNA (mtDNA), while the activities of respiratory chain enzymes remain either normal or mildly affected3. One of the inherited forms of adPEO is caused by specific missense mutations in ANT1, encoding the isoform 1 of the adenine nucleotide translocase (Ant)4. Ant promotes ADP/ATP exchange across the mitochondrial inner membrane. Ant1 knock-out mice accumulate multiple mtDNA deletions in skeletal and cardiac muscles5. Low Ant activity depletes the matrix ADP level. This sequentially causes ATP synthase stagnation, membrane hyperpolarization, increased free radical production and mtDNA damages. Interestingly, mutations in the yeast Aac2p, that mimic the pathogenic adPEO mutations in human Ant1, have only limited effects on its basic nucleotide transport kinetics while dominant-negatively reduce cytochrome content6. The mutant proteins also have a noticeable preference towards the transport of ATP versus ADP. This raises the possibility that, like in the Ant1 knock-out mice, the adPEO-type mutations may also cause adenine nucleotide imbalance in mitochondria thereby leading to mtDNA deletions and respiratory deficiency.

Yeast cannot tolerate over-expression of the aac2A128P allele, equivalent to the human pathogenic ant1A114P, even on glucose medium where respiration is dispensable7. The Ala → Pro mutation might introduce a proline kink and conformational changes at the end of the α-helix 3 in the cytosolic gating region8 (Fig. 1a). When incubated at cold-temperature (25°C), expression of the chromosomally integrated aac2A128P from its native promoter completely inhibit cell growth (Fig. 1b). The cold-sensitivity is also observed in the presence of the wild-type AAC2, supporting the gain-of-function nature of A128P. Aac2A128P is extractable by the detergent NP-40 but not by NaCl or Na2CO3 (Supplementary Information, Fig. S1), indicating that it is integrally inserted into the inner membrane. Cell growth inhibition by Aac2A128P is independent of its ADP/ATP exchange activity, given that the aac2A128P, R252I, aac2A128P, R253I and aac2A128P, R254I double mutants remain cold-sensitive. Arg252, Arg253 and Arg254, equivalent to Arg234, Arg235 and Arg236 in bovine Ant1 (see Fig. 1a), are located in an evolutionarily conserved arginine triplet that acts as a “two-way switch” for nucleotide binding from both sides of the membrane8. Mutations in any of the arginine residues abolish nucleotide transport activity9. As expected, mitochondria expressing aac2A128P, R252I, aac2A128P, R253I and aac2A128P, R254I remain inactive in catalyzing ADP/ATP exchange or in supporting respiratory growth (Supplementary Information, Fig. S2).

Figure 1
The aac2A128P alleles induces defect in mitochondrial biogenesis independent of ADP/ATP exchange activity or mtDNA instability

Incubation of the aac2A128P mutant at 25°C drastically reduces the mitochondrial membrane potential (Δψm) (Supplementary Information, Fig. S3). Mitochondrial depolarization is accompanied with the accumulation of the unprocessed precursor of Hsp60, a nuclear-encoded subunit of the chaperonine complex in the mitochondrial matrix, suggesting that general protein import or proteolytic processing of protein precursors is compromised (Fig. 1c). This is preceded by the loss of the mtDNA-encoded subunit 2 of the cytochrome c oxidase, Cox2p, which may not be synthesised or rapidly degraded because of defective membrane targeting and/or assembly. In these cells, mtDNA profile remains little changed (Fig. 1d), indicating that defects in mitochondrial biogenesis are caused by factors other than mtDNA instability. Massive production of mtDNA mutants can be observed in cells moderately over-expressing aac2A128P (Supplementary Note and Fig. S4). Taken together, our data support that aac2A128P primarily induces defect(s) in general mitochondrial biogenesis by dissipating Δψm. This subsequently compromises mitochondrial gene expression and ultimately, mtDNA stability at a late stage of the degenerative process.

Flow cytometry analysis revealed that a small fraction (2.3%) of diploid cells heterozygous for AAC2/aac2A128P have drastically depolarized mitochondria at 30°C (Fig. 2a). The depolarized cells increase to 23.5% when two copies of aac2A128P were integrated into the genome. In these cultures, mitochondrial depolarization follows a biphasic pattern. In addition to the drastically depolarized cells, the mean fluorescence intensity of the major subpopulation is also reduced by 2.2 fold. The frequency of AAC2/aac2A128P heterozygous cells with severely depolarized mitochondria coincided with the observation that 4.5% of these cells formed barely visible micro-colonies when individually spotted onto YPD medium by micromanipulation (Fig. 2b). These micro-colonies contain maximally 2,000-4,000 cells, in which each cell is incapacitated in producing perpetually proliferating lineages. Thus, after an irreversible mitochondrial damage in each founder cell of a micro-colony, cells progressively degenerate in the following 12-13 cell divisions. We called the progressive loss of the cell's proliferating capability as degenerative cell death, which is a composite phenotype likely instigated by a combination of low Δψm-induced mtDNA mutations and the ρ°-lethal nature of aac2A128P cells (see below).

Figure 2
Aging accelerates mitochondrial degeneration and degenerative cell death

By taking advantage of the phenotypically tractable formation of the degenerative micro-colonies, we asked whether aac2A128P-induced mitochondrial degeneration is aging-dependent. Using pedigree analysis, we determined the commitment to degenerative cell death of all the daughter cells isolated from diploid mothers heterozygous for AAC2/aac2A128P. In most pedigrees, all the daughters formed normal colonies (upper panel; Fig. 2c). However, 5% of the founding mothers produced daughters that formed degenerative micro-colonies (lower panel; Fig. 2c). In these cells, the appearance of the first degenerative daughter was often followed by all her younger siblings, suggesting that after an irreversible commitment in the dividing mother, all the following daughter cells likely inherited the permanently damaged mtDNA, which ultimately limits their proliferating potential.

In haploid cells co-expressing AAC2 and aac2A128P, about 50% of pedigrees were degenerative. Analysis of these pedigrees, which have a median replicative lifespan of 20 generations, revealed that 58.6% of the founding mothers produce their first degenerative daughters after 9-11 cell divisions (Fig. 2d). Mid-age onset is therefore an inherent property of aac2A128P-induced mitochondrial degeneration.

We then directly isolated virgin cells and those that have undergone 5, 10 and 15 cell divisions. These cells of different replicative ages, which co-express AAC2 and aac2A128P, were then individually tested for the degenerative micro-colony formation (Fig. 2e). As age progresses, the micro-colony frequency steadily increases. Degenerative cell death considerably accelerates after the cells are >10 generation old. Thus, aging synergizes with aac2A128P in accelerating mitochondrial degeneration.

We hypothesized that the putative aging-related factor(s) accelerating mitochondrial degeneration may be linked to those that also limit replicative lifespan. If so, mitochondrial degeneration might be delayed by lifespan-extending conditions. To test this, we determined whether a selected panel of currently known lifespan-extending mutations10-14 can suppress aac2A128P. In a steady-state cell population, the defect of aac2A128P cells in forming viable colonies after exposure to 25°C was not suppressed by SIR2 over-expression or fob1Δ (Fig. 3a) which extend replicative lifespan by inhibiting the formation of nucleolar extrachromosomal ribosomal DNA circles (ERCs)14, 15. However, the cold-induced degenerative cell death was significantly suppressed by gpr1Δ and tor1Δ, and almost completely suppressed by sch9Δ, rei1Δ and rpl6BΔ. GPR1 encodes a G protein-coupled receptor upstream of the protein kinase A (PKA) pathway. Together with tor1Δ and sch9Δ, mutations in these three nutrient-sensing kinases promote longevity10, 11. REI1 is involved in ribosomal biogenesis16. RPL6B encodes a component of the 60S ribosomal subunit. These longevity mutations have no significant effect on the expression levels of Aac2p and Aac2A128P (Supplementary Information, Fig. S5).

Figure 3
Longevity interventions suppress mitochondrial degeneration

The suppressor activity can also be directly observed based on growth phenotype at 30°C. For instance, by dissecting diploid strains heterozygous for aac2A128P and rpl6BΔ, aac2A128P-expressing segregants formed small, white and sectoring colonies indicative of cell growth inhibition, whereas double mutants bearing both aac2A128P and rpl6BΔ produced regular red colonies like the wild type spores (Fig. 3b).

Caloric and amino acid restrictions also extend replicative lifespan13, 17. We found that the defect of nascent aac2A128P-expressing meiotic segregants to form viable colonies at 25°C is weakly suppressed by reducing glucose concentration from 2% to 0.5%, and markedly suppressed by growing the cells on minimal synthetic medium lacking most amino acids (Fig. 3c).

Additional lifespan-extending mutations, including tma19Δ18, rpd3Δ19 and rpl31AΔ11 also suppress the cold-induced degenerative cell death in aac2A128P-expressing strains (Fig. 3a). Tma19p (or Mmi1p) affects polysome formation 20. Rpd3p is a histone deacetylase known to affect rRNA processing and ribosomal biogenesis21. Rpl31Ap is a component of the 60S ribosomal subunit.

We next tested whether the longevity interventions can suppress the aging-dependent onset of degenerative cell death. Clearly, the aging-dependent formation of degenerative micro-colonies in aac2A128P cells was dramatically suppressed by rpl6BΔ, rei1Δ, sch9Δ, and caloric restriction (Fig. 3d).

Replicative lifespan analysis also recapitulated an opposing effect between longevity interventions and aac2A128P. The median lifespan of the cell is shortened by an average of 28% (P < 0.005, unpaired student's t test) in aac2A128P-expressing cells compared with the wild type control (Fig. 3e). The median lifespan of aac2A128P cells is extended for 76.5%, 45.0% and 55.5% by rpl6BΔ, rei1Δ and sch9Δ respectively (Wilcoxon Rank-Sum test, P<0.0001). Mitochondrial degeneration is therefore epistatic to rpl6BΔ, rei1Δ and sch9Δ in replicative lifespan control.

Aged yeast cells have low Δψm22. We hypothesized that Aac2A128P may synergise with the aging-dependent decline of Δψm and accelerate mitochondrial degeneration. To support this, we found that aac2A128P cells are hypersensitive to low Δψm conditions. For instance, after meiosis, although aac2A128P segregants can tolerate the loss of mitochondrial ATP synthesis by disrupting ATP1, encoding the α-subunit of the ATP synthase, they are synthetically lethal with the disruption of CYT1 and COX4, encoding components of the complex III and IV in the electron transport chain (Fig. 4a). Expression of aac2A128P is also synthetically lethal with phb1Δ and phb2Δ, which are known to cause low Δψm23. The Phb1 and Phb2 complex has a chaperone-like activity that provides a scaffold in the inner membrane for the assembly of the Δψm-generating respiratory complexes24. The synthetic lethality between aac2A128P and phb1Δ is poorly suppressed by gpr1Δ, moderately suppressed by tor1Δ, and strongly suppressed by sch9Δ, rpl6BΔ and rei1Δ (Fig. 4b). It is also suppressed by lifespan-extending nutritional regimens including caloric and amino acid restrictions (Fig. 4c). The gpr1Δ, tor1Δ, sch9Δ, rpl6BΔ and rei1Δ alleles suppress mitochondrial depolarization in aac2A128P cells grown at both 30°C and 25°C (Supplementary Information, Fig. S3).

Figure 4
Longevity interventions suppress aging-dependent mitochondrial degeneration in prohibitin mutants

Loss of prohibitin accelerates aging in yeast and plants23, 25. We found that longevity interventions can also suppress mitochondrial degeneration in prohibitin mutants independent of aac2A128P. Prohibitin mutants cannot tolerate a further decrease of Δψm caused by mtDNA loss26. The ρ°-lethal phenotype can be suppressed by gpr1Δ, tor1Δ, sch9Δ, rpl6BΔ and rei1Δ (Fig. 4d). Most importantly, aging-dependent formation of degenerative micro-colonies is also a prominent phenotypic manifestation of phb1Δ, which is suppressed by sch9Δ, rpl6BΔ, rei1Δ and caloric restriction (Fig. 4e). Thus, degenerative cell death appears to be a common phenotypic manifestation of low Δψm cells. Suppression of aging-dependent mitochondrial degeneration is an intrinsic property of the longevity interventions.

A common property shared by the suppressor mutations is their connection with cytosolic protein synthesis. We speculated that a reduction of cytosolic protein synthesis may lower the overall loading of proteins onto the mitochondrial inner membrane and promote Δψm maintenance in aged aac2A128P and phb1Δ cells. To support this, we first found that the longevity mutations having the strongest phenotypes for suppressing mitochondrial degeneration, namely sch9Δ, rei1Δ, rpl6BΔ and rpl31AΔ (see Fig. 3a), also have the most pronounced effects on cytosolic protein synthesis (Fig. 5a). Conditions such as caloric and amino acid restrictions that have different capacity to suppress cold-induced degenerative cell death (Fig. 3c) also differ in cytosolic protein synthesis (Supplementary information, Fig. S5). Secondly, aac2A128P is synthetically lethal with the disruption of YME1 (Fig. 5b) encoding the i-AAA protease for protein turnover27. yme1Δ does not significantly affect Aac2p level (Supplementary Information, Fig. S5) but is known to cause protein over-accumulation on the inner membrane28. The yme1Δ–induced lethality in aac2A128P cells is suppressed by sch9Δ, rpl6BΔ and rei1Δ. Finally, we demonstrated that partial inhibition of cytosolic protein synthesis by cycloheximide (Fig. 5a) phenocopies the longevity interventions in suppressing the cold-induced growth inhibition (Fig. 5c) and the synthetic lethality between yme1Δ and aac2A128P (Fig. 5b). Cycloheximide, as well as rpl6BΔ, sch9Δ and rei1Δ, can all suppress the cold-induced loss of Cox2p in aac2A128P cells (Fig. 5d). The relative suppressor activity of rpl6BΔ, sch9Δ and rei1Δ correlates with the extent by which they affect cytosolic protein synthesis (Fig. 5a).

Figure 5
Modulation of aac2A128P-induced cell death by mitochondrial protein loading

In summary, in the yeast adPEO model and the pro-aging phb1Δ mutant, we found that reduced cytosolic protein synthesis suppresses mitochondrial degeneration. Like the prohibitin mutants, aac2A128P-expressing cells have low Δψm and shortened replicative lifespan. Ant has an intrinsic membrane uncoupling activity independent of its ADP/ATP exchange function29. A128P may increase such a proton-conducting activity and actively depolarise the membrane, which leads to defects in general mitochondrial biogenesis and mtDNA instability. We captured an aging-dependent trait that accelerates mitochondrial degeneration in replicatively aged aac2A128P and phb1Δ cells. In these mutants, the virgin cells have a low frequency of degenerative cell death, but cell death progressively increases during replicative aging. This aging-dependent deleterious trait likely reflects a progressive decline of Δψm. It is suppressed by reduced cytosolic protein synthesis that may alleviate mitochondria from unassembled protein stress and reduce non-specific proton leakage across the inner membrane during aging (Supplementary Discussion).

The finding that reduced cytosolic protein synthesis robustly promotes mitochondrial maintenance during aging is reminiscent of the observations that longevity interventions not only delay aging-related pathologies, but also improve mitochondrial bioenergetic efficiency and increase stress resistance30-32. Our finding is also consistent with the observation that reduced TOR signalling maintains the robustness of the mitochondrial gene expression system and stimulates mitochondrial respiration33. Recent studies from several model organisms have shown that reduced cytosolic protein translation directly extends lifespan34. In yeast, reduction of the cytosolic ribosomal subunits and altered translation also promote longevity11, 12, 35. One of the underlying mechanisms is that specific translational alterations selectively change the expression of proteins such as the transcriptional factor Gcn4, which may benefit cell survival12. Our finding therefore opens the possibility that aged cells also benefit from reduced cytosolic protein synthesis by improving energy homeostasis.

Methods

Strains and media

Yeast strains used in this study are listed in Supplementary Information Table S1. Details for strain construction, plasmids and growth media are provided in Supplementary Methods.

Replicative lifespan and pedigree analysis

Yeast strains were grown in YPD at 30°C for overnight and seeded on YPD plates using an inoculation loop. Individual cells were arrayed on YPD plates by using a Singer yeast tetrad dissector and allowed to divide for 1-2 divisions. Virgin cells were retained for lifespan analysis. Subsequent daughter cells were removed and counted. All micromanipulations were carried out in a room conditioned at 26°C. For lifespan analysis, about 50 cells were examined for each strain. A wild type strain is always examined in parallel to mutant strains, in order to minimize fluctuations of environmental factors that may influence data output. For pedigree analysis, only two virgin cells were analyzed on each plate. All the daughter cells generated were orderly arrayed. Cells were grown at 30°C during the day and stored at 4°C at night.

Degenerative micro-colony assay

For assaying micro-colony formation of cells in a steady state cell population, a fresh colony from YPD plates is inoculated in 5 ml YPD medium. After a growth for 15 hours at 25°C, cells were patched on YPD plates. 90 individual cells were arrayed onto fresh spots for colony formation. Cells were incubated at 30°C for five days. All the arrayed spots were inspected under microscopy for degenerative micro-colonies. Degenerative micro-colonies were defined for those that contain 4 – 4,000 cells after the 5-day incubation. The ratios of degenerative micro-colonies over total number of dividing cells were calculated. For examining aging-dependent micro-colony formation, precultures were grown in YPD at 30°C. Cells were arrayed on YPD. Virgin cells were prepared and allowed to form colonies (0 generation). Virgin cells were also allowed to divide and the generated daughter cells were removed. The removal of daughter cells was stopped after 5, 10 and 15 cell divisions, resulting cells of 5-, 10- and 15-generation old respectively. The mother cells of defined ages were allowed to form colonies at 30°C. The ratios of degenerative micro-colonies over total number of seeded cells were calculated.

Protein synthesis assay

Overnight YPD-grown cultures were diluted into synthetic complete medium lacking methionine to reach an OD600 of ~0.5. Cells were grown for 3 hours at 30°C or 25°C. The OD600 of the cultures were measured to determine cell numbers. 1 ml of the cultures were labelled with 6 μCi/ml [35S]-methionine/cysteine (EXPRE35S35S Protein Labeling Mix; >1000 Ci/mmol; NEN Research Products) for 5-30 min at 30°C or 25°C. Labelling was stopped by the addition of 1/10 volume of 100% TCA to each culture and chilling on ice. After heating at 90°C for 20 min, TCA precipitates were collected on GFC filters (Whatman), washed sequentially with 10 ml of 10% TCA and 95% ethanol, and counted in 5 ml of UniverSol (ICN). For each sample, the counts per minute/OD600 was normalized to wild type which is set as 100%. Three independent experiments were carried out with the error bars representing the standard deviation. The P-values shown were determined using unpaired Student's t test.

Supplementary Material

Supplement

Acknowledgments

We thank M. Schmitt and M. Kucej for critical reading on the manuscript, and L. Sabova and C. Koehler for providing the anti-Aac2 antibody. This work was supported by grants from National Institute of Health (AG023731) and the American Heart Association (0435047N).

Footnotes

Note: Supplementary Information is available on the Nature Cell Biology website.

Author Information: The authors declare no competing financial interests. X.W., X.Z., B.K. and X.J.C. performed experiments; X.J.C. designed experiments, analyzed data and wrote the manuscript. All authors discussed the results and commented on the manuscript.

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