Mitochondrial Health: How Testosterone Affects Cellular Energy

A patient told me last spring that he'd stopped taking the stairs at work. Not because his knees hurt. Not because he was out of shape, exactly. He just got to the third-floor landing and felt like something inside him had quietly run out. He was 44, his labs were "fine" according to the physical he'd had in January, and he described the feeling the way most men do: "I don't feel sick. I just don't have anything left in the tank."

That phrase comes up constantly in my practice. The tank. And it's a better metaphor than most patients realize, because the thing they're describing usually isn't willpower or discipline or getting older. It's energy production at the cellular level. I'm Dr. Farhan Abdullah, an internal medicine physician and the medical director at Magnolia Functional Wellness here in Southlake, and I still work hospital shifts in Dallas, which means I see the far end of this spectrum regularly. The men who land on my hospital service with heart failure and metabolic disease didn't get there overnight. They spent a decade or two feeling like the tank was empty and being told their labs looked fine.

So let's talk about mitochondria, and specifically about what testosterone has to do with them. This is one of the more genuinely interesting corners of hormone medicine, and also one where the internet has gotten well ahead of the evidence.

What Your Mitochondria Actually Do All Day

Every cell in your body that needs meaningful amounts of energy contains mitochondria. Muscle cells are packed with them. So are heart cells, liver cells, and neurons. Red blood cells have none, which is part of why they're such simple little things.

The job is straightforward to describe and remarkably elegant in execution. Mitochondria take the fuel you eat, mostly fat and glucose, strip electrons off it, and run those electrons down a chain of protein complexes embedded in the inner mitochondrial membrane. As electrons move down that chain, protons get pumped across the membrane, building a gradient. When those protons flow back through an enzyme called ATP synthase, you get ATP, the molecule that powers essentially every process in your body that costs something.

Here's the part worth sitting with: you produce and consume roughly your own body weight in ATP every single day. Not because you store that much. Because you recycle it constantly. Your entire ATP pool turns over every minute or two.

Which means that when someone says they have no energy, they may be describing something quite literal. Not a mood. Not motivation. A throughput problem in the machinery that makes their body's currency.

Mitochondria aren't static, either. They divide, fuse, get recycled when damaged (a process called mitophagy), and get built new through a process called mitochondrial biogenesis. The master regulator of that construction process is a protein with an unfortunate name: PGC-1 alpha. When PGC-1 alpha activity is high, you build more mitochondria and better ones. When it drops, you don't.

Where Testosterone Enters the Picture

Androgen receptors sit in the nuclei of muscle cells, neurons, and cardiomyocytes, among others. When testosterone binds them, it changes which genes get transcribed. Some of those genes are structural. Some of them govern how mitochondria are built and maintained.

The animal work here is more informative than most people assume. A 2014 study in the Journal of Molecular Neuroscience examined what happens when brain testosterone is depleted, and found down-regulation of mitochondrial gene expression in the rat hippocampus, alongside a decline in PGC-1 alpha expression. Take away the androgen signal, and the cell's blueprint for building mitochondria gets quieter. Not destroyed. Quieter.

A larger 2021 paper in Aging approached it from the other direction, reporting that testosterone ameliorates age-related brain mitochondrial dysfunction in an aged animal model. Restore the signal, and some of that bioenergetic capacity comes back.

I want to be careful here, because this is exactly where wellness marketing tends to skip a step. Those are animal studies. Rodent hippocampus is not a 44-year-old man's quadriceps, and "improved mitochondrial gene expression in mice" is a mechanistic finding, not a promise about how you'll feel on a Tuesday afternoon. What these studies establish is plausibility and a pathway. They don't establish clinical magnitude.

For the human side, the most rigorous recent synthesis I've read is a 2026 review in Endocrine Reviews on the mechanisms of testosterone's anabolic effects on muscle and function. The title includes the word "controversies," which tells you something about the state of the field. Testosterone reliably increases muscle mass in men. Exactly how much of that translates into better function, better endurance, better cellular energetics rather than simply more tissue, is still being argued over by people who know far more about it than the average podcast host.

Why More Muscle Is Also More Mitochondria

There's an indirect route that gets overlooked, and in my view it's at least as important as the direct receptor-level story.

Skeletal muscle is your largest reservoir of mitochondria. When testosterone increases lean mass, particularly when it's paired with resistance training, you aren't just adding contractile tissue. You're adding mitochondrial real estate. More muscle means more capacity to oxidize fat and glucose, better insulin sensitivity, more resting energy expenditure, and a larger metabolic buffer for everything else your body has to do.

Run that in reverse and you get the pattern I see constantly. Testosterone drifts down. Muscle mass drifts down with it. Visceral fat goes up. Insulin resistance creeps in, which impairs how efficiently mitochondria handle substrate. Fatigue increases, so activity decreases, so muscle drops further. It's a loop, and it's slow enough that most men experience it as normal aging rather than as a physiological process with identifiable levers.

Sleep sits inside that loop too. Poor sleep suppresses testosterone production, and untreated sleep apnea does it aggressively. I've had patients convinced they needed hormone therapy who mostly needed a sleep study. That conversation isn't as satisfying as writing a prescription, but it's the right one.

What Testosterone Therapy Actually Delivered in the Trials

Here's where I have to disappoint the more enthusiastic version of this story.

The Testosterone Trials, published in the New England Journal of Medicine in 2016, remain the most careful look we have at symptomatic outcomes in older men with genuinely low levels. That paper, Effects of Testosterone Treatment in Older Men, found clear benefit for sexual function. The vitality outcome, which is the one every fatigued patient cares about most, was considerably more modest. Men reported walking further and feeling somewhat better overall, but the vitality signal did not reach the threshold the investigators had set.

I bring this up deliberately, because it's the honest framing. If someone tells you testosterone therapy will restore your energy the way a jump start restores a dead battery, they're overselling it. What the evidence supports is narrower and more useful: in men with confirmed, symptomatic deficiency, restoring physiologic levels removes a biological constraint. It doesn't manufacture energy out of nothing. It stops one particular thing from actively holding you back.

In my practice, the men who do best on testosterone replacement therapy are almost never the men who did nothing else. They're the ones who started lifting twice a week, fixed their sleep, got their thyroid looked at properly, and treated hormone optimization as one input among several. The guy who wants the injection and no other changes is usually the guy who tells me at three months that he doesn't feel much different.

The Other Things I Check Before Blaming Hormones

When a man walks into the clinic in Southlake describing the empty-tank feeling, testosterone is on my list. It is not the top of my list. Cellular energy has more than one failure point, and I'd rather find the real one.

• Thyroid function, properly assessed. Thyroid hormone regulates mitochondrial density and metabolic rate across essentially every tissue. A TSH of 4.7 with a free T3 scraping the bottom of the range is not a normal thyroid, whatever the lab report's reference range implies.
• Iron and ferritin. You cannot run an electron transport chain without iron-sulfur clusters. I've seen men with ferritin in the teens told their hemoglobin was normal, so nothing was wrong. Something was wrong.
• B12 and folate. Cheap to check, occasionally the whole answer.
• Sleep apnea. Especially in men carrying extra weight around the neck and midsection. This is the single most commonly missed cause of the complaint I'm describing.
• Blood sugar and insulin. Not just fasting glucose. Insulin resistance degrades mitochondrial substrate handling long before anyone's A1c crosses a diagnostic line.
• NAD+ availability. The electron transport chain needs NAD+ to accept electrons upstream, and levels decline with age. For patients whose primary complaint is fatigue rather than body composition, NAD+ therapy sometimes addresses the bottleneck more directly than anything hormonal would.

Notice how many of those are ordinary internal medicine. That's not an accident. The functional medicine training I did through IFM sharpened how I think about upstream causes, but the actual work of sorting out fatigue is still mostly careful, unglamorous diagnostics.

What I'd Want You to Take From This

Mitochondrial biology is real, and testosterone genuinely participates in it. The receptor pathways exist, the animal data are consistent, and the muscle-mass mechanism is straightforward and well established. If your testosterone is low and you feel like the tank is empty, those two facts are probably related.

But the relationship is a gradient, not a switch. Testosterone isn't a mitochondrial supplement, and anyone marketing it as one has moved past what the evidence supports. The realistic version is that hormone optimization removes one meaningful drag on your cellular energy economy, and the size of that effect depends heavily on what else is going on.

My advice to the man who stopped taking the stairs is the same advice I'd give you. Get the full picture before you accept an explanation. Morning total and free testosterone, yes, but also thyroid with free T3, ferritin, a metabolic panel, fasting insulin, and an honest conversation about how you're actually sleeping. If testosterone turns out to be the problem, we treat it and we monitor it properly. If it isn't, you've saved yourself from optimizing a number that was never the issue.

That's the approach we take at Magnolia Functional Wellness in Southlake, and honestly, it's the approach I'd want if I were the one on the third-floor landing wondering where my energy went.

By Dr. Farhan Abdullah, DO | Medical Director, Magnolia Functional Wellness | Southlake, TX